Heterocyclic derivatives

ABSTRACT

The invention concerns a heterocyclic derivative of the formula I, ##STR1## wherein Ar 1  is optionally substituted phenyl or naphthyl; 
     A 1  is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo-(3-6C)alkylene; 
     Ar 2  is optionally substituted phenylene, or a 6 membered heterocyclene moiety containing up to three nitrogen atoms; 
     R 1  is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and 
     R 2  and R 3  together form a group of the formula -A 2  -X-A 3  - wherein each of A 2  and A 3  is (1-4C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino; 
     or a pharmaceutically-acceptable salt thereof. 
     The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

This invention concerns novel heterocyclic derivatives and moreparticularly novel heterocyclic derivatives which are inhibitors of theenzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The inventionalso concerns processes for the manufacture of said derivatives andnovel pharmaceutical compositions containing said derivatives. Alsoincluded in the invention is the use of said derivatives in thetreatment of various inflammatory and/or allergic diseases in which thedirect or indirect products of 5-LO catalysed oxidation of arachidonicacid are involved, and the production of new medicaments for such use.

As stated above the heterocyclic derivatives described hereinafter areinhibitors of 5-LO, which enzyme is known to be involved in catalysingthe oxidation of arachidonic acid to give rise via a cascade process tothe physiologically active leukotrienes such as leukotriene B₄ (LTB₄)and the peptido-lipid leukotrienes such as leukotriene C₄ (LTC₄) andleukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trendsin Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes andtheir metabolites have been implicated in the production and developmentof various inflammatory and allergic diseases such as arthriticdiseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis,cardiovascular and cerebrovascular disorders and inflammatory boweldisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolites of arachidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

We have now discovered that certain heterocyclic derivatives areeffective as inhibitors of the enzyme 5-LO and thus of leukotrienebiosyntheses. Thus, such compounds are of value as therapeutic agents inthe treatment of, for example, allergic conditions, psoriasis, asthma,cardiovascular and cerebrovascular disorders, and/or inflammatory andarthritic conditions, mediated alone or in part by one or moreleukotrienes.

According to the invention there is provided a heterocylic derivative ofthe formula I (set out hereinafter)

wherein Ar¹ is phenyl or naphthyl which may optionally bear one or moresubstituents selected from amino, halogeno, hydroxy, carboxy, cyano,(1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkysulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl,(2-4C)alkanoyl, (2-4C)alkanoylamino, hydroxy-(1-4C)alkyl,fluoro-(1-4C)alkyl, amino-(1-4C)alkyl, cyano-(1-4C)alkyl andcyano-(1-4C)alkoxy; wherein A¹ is (1-6C)alkylene, (3-6C)alkenylene,(3-6C)alkynylene or cyclo(3-6C)alkylene;

wherein Ar² is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, ureido, (1-4C)alkyl, (3-4C)alkenyloxy, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl,(1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy,hydroxy-(2-4C)alkylamino, cyano-(1-4C)alkylamino,carboxy-(1-4C)alkylamino and (1-4C)alkoxycarbonyl-(1-4C)alkylamino; orAr² is a 6-membered heterocyclene moiety containing up to three nitrogenatoms; wherein R¹ is hydrogen, (1-6C)alkyl, (3-6C)alkenyl,(3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoylwhich may optionally bear a substituent selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy; and

wherein R² and R³ together form a group of the formula -A² -X-A³ -which,together with the carbon atom to which A² and A³ are attached, defines aring having 4 to 7 ring atoms, wherein A² and A³, which may be the sameor different, each is (1-4C)alkylene and X is oxy, thio, sulphinyl,sulphonyl or imino, and which ring may bear one, two or threesubstituents, which may be the same or different, selected from hydroxy,(1-4C)alkyl, (1-4C)alkoxy, (3-4C)alkenyloxy and (3-4C)alkynyloxy;

or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as "propyl" are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as "isopropyl" are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds offormula I defined above may exist in optically active or racemic formsby virtue of one or more substituents containing an asymmetric carbonatom, the invention includes in its definition of active ingredient anysuch optically active or racemic form which possesses the property ofinhibiting 5-LO. The synthesis of optically active forms may be carriedout by standard techniques of organic chemistry well known in the art,for example by synthesis from optically active starting materials or byresolution of a racemic form. Similarly, inhibitory properties against5-LO may be evaluated using the standard laboratory techniques referredto hereinafter.

Suitable values for the generic terms referred to above include thoseset out below.

A suitable value for a halogeno substituent which may be present on Ar¹,Ar² or R¹ is, for example, fluoro, chloro, bromo or iodo.

A suitable value for a (1-6C)alkyl substituent which may be present onAr¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl.

A suitable value for a (1-4C)alkyl substituent which may be present onAr² or R¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl or sec-butyl.

A suitable value for a (2-6C)alkenyl substituent on Ar¹ is, for example,vinyl, allyl, 2-butenyl or 3-butenyl.

A suitable value for a (2-6C)alkynyl substituent on Ar¹ is, for example,ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl.

A suitable value for a (1-4C)alkoxy substituent which may be present onAr¹, Ar² or R¹ is, for example, methoxy, ethoxy, propoxy, isopropoxy orbutoxy.

A suitable value for a (2-4C)alkanoyl substituent which may be presenton Ar¹ or for R¹ when it is (2-4C)alkanoyl is, for example acetyl,propionyl or butyryl.

Suitable values for substituents which may be present on Ar¹ or Ar²include, for example:

for (1-4C)alkylthio: methylthio, ethylthio, propylthio, isopropylthioand butylthio;

for (1-4C)alkylsulphinyl: methylsulphinyl, ethylsulphinyl,propylsulphinyl, isopropylsulphinyl and butylsulphinyl;

for (1-4C)alkylsulphonyl: methysulphonyl, ethylsulphonyl,propylsulphonyl, isopropylsulphonyl and butylsulphonyl;

for (1-4C)alkylamino: methylamino, ethylamino propylamino andbutylamino;

for di-[(1-4C)alkyl]amino: dimethylamino, diethylamino anddipropylamino;

for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl andtert-butoxycarbonyl;

for fluoro-(1-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;

for cyano-(1-4C)alkoxy: cyanomethoxy, 2-cyanoethoxy and 3-cyanopropoxy;

for (2-4C)alkanoylamino: acetamido, propionamido and butyramido.

A suitable value for a substituent which may be present on Ar¹ when itis hydroxy-(1-4C)alkyl is, for example, hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl or 3-hydroxypropyl;when it is cyano-(1-4C)alkyl is, for example, cyanomethyl, 1-cyanoethyl,2-cyanoethyl, 3-cyanopropyl or 2-cyanoprop-2-yl; and when it isamino-(1-4C)alkyl is, for example, aminomethyl, 2-aminoethyl or3-aminopropyl.

A suitable value for the number of substituents which may be present onAr¹ is, for example, one, two or three.

A suitable value for A¹ when it is (1-6C)alkylene is, for example,methylene, ethylene, ethylidene, trimethylene, propylidene,tetramethylene or pentamethylene; when it is (3-6C)alkenylene is, forexample, 1-propenylene, 2-methylprop-1-enylene, 3-methylprop-1-enylene,1-butenylene or 2-butenylene; and when it is (3-6C)alkynylene is, forexample, 1-propynylene, 3-methylprop-1-enylene, 1-butynylene or2-butynylene.

A suitable value for A¹ when it is cyclo(3-6C)alkylene is, for example,cyclopropylidene, 1,2-cyclopropylene, cyclopentylidene,1,2-cyclopentylene, cyclohexylidene or 1,4-cyclohexylene.

A suitable value for Ar² when it is phenylene is, for example,1,3-phenylene or 1,4-phenylene.

A suitable value for Ar² when it is a 6-membered heterocyclene moietycontaining up to three nitrogen atoms is, for example, pyridylene,pyrimidinylene, pyridazinylene, pyrazinylene or 1,3,5-triazinylene.Conveniently Ar² when it is a 6-membered heterocyclene moiety containingup to three nitrogen atoms is, for example, 2,4-, 2,5-, 3,5- or2,6-pyridylene, 2,4-, 2,5- or 4,6-pyrimidinylene, 3,5- or3,6-pyridazinylene or 2,5- or 2,6-pyrazinylene.

Suitable values for substituents which may be present on Ar² include,for example:

for (3-4C)alkenyloxy: allyloxy, methylallyoxy, but-2-enyloxy andbut-3-enyloxy;

for N-[(1-4C)alkyl]carbamoyl: N-methylcarbamoyl, N-ethyl-carbamoyl andN-propylcarbamoyl;

for N,N-di-[(1-4C)alkyl]-carbamoyl: N,N-dimethylcarbamoyl andN,N-diethylcarbamoyl;

for carbamoyl-(1-4C)alkoxy; carbamoylmethoxy, 2-carbamoyl ethoxy and3-carbamoyl propoxy;

for (1-4C)alkoxycarbonyl-(1-4C)-alkoxy: methoxycarbonylmethoxy,2-methoxycarbonylethoxy, ethoxycarbonylmethoxy and2-ethoxycarbonylethoxy.

for hydroxy-(2-4C)alkylamino: 2-hydroxyethylamino, 3-hydroxyproplyaminoand 4-hydroxyalkylamino;

for cyano-(1-4C)alkylamino: cyanomethylamino, 2-cyanoethylamino and3-cyanopropylamino;

for carboxy-(1-4C)alkylamino: carboxymethylamino, 2-carboxyethylaminoand 3-carboxypropylamino;

for (1-4C)alkoxycarbonyl-(1-4C)alkylamino: methoxycarbonylmethylamino,ethoxycarbonylmethylamino, 2-methoxycarbonylethylamino and2-ethoxycarbonylethylamino.

A suitable value for R¹ when it is (1-6C)alkyl is, for example, methyl,ethyl, propyl, butyl, pentyl or hexyl.

A suitable value for R¹ when it is (3-6C)alkenyl is, for example, allyl,2-butenyl or 3-butenyl; and when it is (3-6C)alkynyl is, for example,2-propynyl or 2-butynyl.

A suitable value for R¹ when it is cyano-(1-4C)alkyl is, for example,cyanomethyl, 2-cyanoethyl or 3-cyanopropyl.

When R² and R³ together form a group of the formula -A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 4 to 7 ring atoms then a a suitable value for A² or A³,which may be the same or different, when each is (1-4C)alkylene is, forexample, methylene, ethylene, trimethylene or tetramethylene.

Suitable values for the one, two or three substituents which may bepresent on said 4- to 7-membered ring included for example:

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and butyl;

for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for (3-4C)alkenyloxy: allyloxy, methylallyloxy and but-2-enyloxy;

for (3-4C)alkynyloxy: 2-propynyloxy and 2-butynyloxy.

When R² and R³ together form a group of the formula -A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 4 to 7 ring atoms, and when said ring bears one, two orthree (1-4C)alkyl substituents, then suitable values for the(1-4C)alkyl-substituted A² and A³ groups include, for example,ethylidene, propylidene, isopropylidene, propylene,2-methyltrimethylene, but-1,2-diyl, 2-methylprop-1,2-diyl, pent-1,2-diyland hex-1,2-diyl.

A suitable pharmaceutically-acceptable salt of a heterocyclic derivativeof the invention which is sufficiently basic is an acid-addition saltwith, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a heterocyclic derivative of theinvention which is sufficiently acidic (for example a heterocyclicderivative of the invention which contains a carboxy group) is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically-acceptablecation, for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

According to a further aspect of the invention there is provided aheterocyclic derivative of the formula I

wherein Ar¹ is phenyl or naphthyl which may optionally bear one or moresubstituents selected from halogeno, hydroxy, carboxy, cyano,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkysulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl,(2-4C)alkanoyl, hydroxy-(1-4C)alkyl and fluoro-(1-4C)alkyl;

wherein A¹ is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkenylene orcyclo(3-6C)alkylene;

wherein Ar² is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, (1-4C)alkyl, (3-4C)alkenyl, (1-4C)alkoxy, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkysulphonyl, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl, (1-4C)alkoxycarbonyl,N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,(2-4C)alkanoylamino, cyano-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy and(1-4C)alkoxycarbonyl-(1-4C)alkoxy; or Ar² is a 6-membered heterocyclenemoiety containing up to three nitrogen atoms;

wherein R¹ is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl,cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoyl which mayoptionally bear a substituent selected from halogeno, (1-4C)alkyl and(1-4C)alkoxy; and

wherein R² and R³ together form a group of the formula -A² -X-A³ -which, together with the carbon atom to which A² and A³ are attached,defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may bethe same or different, each is (1-4C)alkylene and X is oxy, thio,sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable saltthereof.

When, as defined immediately above, R² and R³ together form a group ofthe formula -A² -X-A³ - which, together with the carbon atom to which A²and A³ are attached, defines a ring having 5 to 7 ring atoms then asuitable value for A² or A³, which may be the same or different, wheneach is (1-4C)alkylene is, for example, methylene, ethylene, ethylidene,trimethylene, propylidene, isopropylidene, propylene,2-methyltrimethylene, tetramethylene, but-1,2-diyl or but-1,3-diyl.

Particular novel compounds of the invention are, for example,heterocyclic derivatives of the formula I wherein:

(a) Ar¹ is phenyl, naphth-1-yl or naphth-2-yl which may optionally bearone, two or three substituents selected from amino, fluoro, chloro,bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,methoxy, methylthio, methylsulphinyl, methylsulphonyl, methoxycarbonyl,acetamido, difluoromethyl, trifluoromethyl, aminomethyl, cyanomethyl,1-cyanoethyl, 2-cyanoprop-2-yl, cyanomethoxy and 2-cyanoethoxy; and A¹,Ar², R¹, R² and R³ have any of the meanings defined hereinbefore;

(b) Ar¹ is phenyl, naphth-1-yl or naphth-2-yl which may optionally bearone, two or three substituents selected from fluoro, chloro, bromo,iodo, cyano, methyl, methoxy, methylthio, methylsulphinyl,methylsulphonyl, methoxycarbonyl, difluoromethyl and trifluoromethyl;and A¹, Ar², R¹, R² and R³ have any of the meanings definedhereinbefore;

(c) A¹ is methylene, ethylene, trimethylene, 1-propenylene,2-methylprop-1-enylene or 1-propynylene and Ar¹, Ar², R¹, R² and R³ haveany of the meanings defined hereinbefore;

(d) Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, chloro, bromo, hydroxy, amino, nitro,cyano, carbamoyl, ureido, methyl, methoxy, allyloxy, methylthio,methylsulphinyl, methylsulphonyl, methylamino, dimethylamino,trifluoromethyl, acetamido, cyanomethoxy, carbamoylmethoxy,2-hydroxyethylamino, cyanomethylamino, carboxymethylamino,methoxycarbonylmethylamino and ethoxycarbonylmethylamino; and Ar¹, A¹,X, R¹, R² and R³ have any of the meanings defined hereinbefore;

(e) Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, chloro, bromo, hydroxy, amino, nitro,methyl, methoxy, allyloxy, methylthio, methylsulphinyl, methylsulphonyl,methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy andcarbamoylmethoxy and Ar¹, A¹, X, R¹, R² and R³ have any of the meaningsdefined hereinbefore;

(f) Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from chloro, bromo, hydroxy, amino, nitro, methyl,methoxy, allyloxy, methylthio, methylsulphinyl, methylsulphonyl,methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy andcarbamoylmethoxy and Ar¹, A¹, X, R¹, R² and R³ have any of the meaningsdefined hereinbefore;

(g) Ar² is 3,5-pyridylene or 3,5-pyridazinylene; and Ar¹, A¹, R¹, R² andR³ have any of the meanings defined hereinbefore;

(h) Ar² is 2,4-, 2,5-, 3,5- or 2,6-pyridylene or 4,6-pyrimidinylene; andAr¹, A¹, R¹, R² and R³ have any of the meanings defined hereinbefore;

(i) R¹ is hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl orcyanomethyl; and Ar¹, A¹, Ar², R² and R³ have any of the meaningsdefined hereinbefore;

(j) R¹ is hydrogen, methyl, ethyl, allyl, 2-propynyl or cyanomethyl; andAr¹, A¹, Ar², R² and R³ have any of the meanings defined hereinbefore;

(k) R² and R³ together form a group of the formula -A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 4 to 7 ring atoms, wherein A² and A³, which may be the sameor different, each is methylene, ethylene, trimethylene ortetramethylene and X is oxy, thio, sulphinyl or sulphonyl, and whichring may bear one or two substituents, which may be the same ordifferent, selected from hydroxy, methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, allyloxy and 2-propynyloxy; and Ar¹, A¹, Ar² and R¹have any of the meanings defined hereinbefore;

(l) R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 4 to 7 ring atoms, and said ring bears one or two(1-4C)alkyl substituents such that particular values for the (1-4C)alkylsubstituted A² and A³ groups, include, for example, ethylidene,isopropylidene, propylene, but-1,2-diyl, 2-methylprop-1,2-diyl andpent-1,2-diyl; and Ar¹, A¹, Ar² and R¹ have any of the meanings definedhereinbefore;

(m) R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 7 ring atoms, wherein A² and A³, which may be the sameor different, each is methylene, ethylene, ethylidene, trimethylene,propylene or tetramethylene and X is oxy, thio, sulphinyl or sulphonyl;and Ar¹, A¹, Ar² and R¹ have any of the meanings defined hereinbefore;or

(n) R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 7 ring atoms, wherein A² and A³, which may be the sameor different, each is methylene, ethylene, ethylidene, trimethylene ortetramethylene and X is oxy, thio, sulphinyl or sulphonyl; and Ar¹, A¹,Ar² and R¹ have any of the meanings defined hereinbefore;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a heterocyclicderivative of the formula I wherein

Ar¹ is phenyl or naphth-2-yl which may optionally bear one or twosubstituents selected from amino, fluoro, chloro, bromo, cyano, methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, methylthio,methylsulphinyl, methylsulphonyl, difluoromethyl, trifluoromethyl,cyanomethyl, 1-cyanoethyl, 2-cyanoprop-2-yl, cyanomethoxy and2-cyanoethoxy;

A¹ is methylene, 1-propenylene or 1-propynylene;

Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, hydroxy, amino, nitro, ureido,methoxy, methylamino, dimethylamino, trifluoromethyl, acetamido,cyanomethoxy, 2-hydroxyethylamino, cyanomethylamino andcarboxymethylamino; or

Ar² is 3,5-pyridylene or 3,5-pyridazinylene;

R¹ is hydrogen, methyl, ethyl, allyl or 2-propynyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 7 ring atoms, wherein A² is ethylene, A³ is methylene,ethylene or trimethylene, and X is oxy or thio, and which ring may bearone or two substituents, which may be the same or different, selectedfrom hydroxy, methyl, ethyl, propyl and methoxy; or apharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a heterocyclicderivative of the formula I wherein Ar¹ is phenyl or naphth-2-yl whichmay optionally bear one or two substituents selected from fluoro,chloro, bromo, cyano, methyl, ethyl, tert-butyl, methylthio,methylsulphinyl, difluoromethyl, trifluoromethyl and cyanomethoxy;

A¹ is methylene or 1-propynylene;

Ar² is 1,3-phenylene which may optionally bear one substituent selectedfrom fluoro, amino, nitro, ureido, dimethylamino, trifluoromethyl andcyanomethylamino; or Ar² is 3,5-pyridylene;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 6 ring atoms, wherein A² is ethylene, A³ is methyleneor ethylene and X is oxy, and which ring may bear a methyl or ethylsubstituent alpha to X;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a heterocyclicderivative of the formula I wherein

Ar¹ is phenyl, naphth-1-yl or naphth-2-yl which may optionally bear oneor two substituents selected from fluoro, chloro, cyano, methyl,methoxy, difluoromethyl and trifluoromethyl;

A¹ is methylene, 1-propenylene or 1-propynylene;

Ar² is 1,3-phenylene or 1,4-phenylene which may optionally bear onesubstituent selected from fluoro, hydroxy, amino, nitro, methoxy,methylamino, cyanomethoxy and trifluoromethyl; or

Ar² is 3,5-pyridylene; and

R¹ is hydrogen, methyl, allyl or cyanomethyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene,ethylene, ethylidene, trimethylene, propylene or tetramethylene and X isoxy or thio; or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a heterocyclicderivative of the formula I wherein

Ar¹ is naphth-2-yl;

A¹ is methylene;

Ar² is 1,3-phenylene;

R¹ is hydrogen or methyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene,ethylene or ethylidene and X is oxy or thio; or apharmaceutically-acceptable salt thereof.

An especially preferred compound of the invention comprises aheterocyclic derivative of the formula I wherein

Ar¹ is phenyl or naphth-2-yl; A¹ is methylene or 1-propynylene;

Ar² is 1,3-phenylene or 5-fluoro-1,3-phenylene;

R¹ is methyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is ethylene,ethylidene or propylene and X is oxy; or a pharmaceutically-acceptablesalt thereof.

A further especially preferred compound of the invention comprises aheterocyclic derivative of the formula I wherein

Ar¹ is phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl,3-chlorophenyl, 3,5-dichlorophenyl, 2,5-dimethylphenyl, 4-ethylphenyl,4-tert-butylphenyl, 4-methylthiophenyl, 4-methylsulphinylphenyl,2-trifluoromethylphenyl, 2-cyanomethoxyphenyl, 3-cyanomethoxyphenyl,2-cyano-3-fluorophenyl or 2-methylthio-5-trifluoromethylphenyl;

A¹ is 1-propynylene;

Ar² is 1,3-phenylene, 5-fluoro-1,3-phenylene, 5-amino-1,3-phenylene,5-nitro-1,3-phenylene, 5-ureido-1,3-phenylene,5-dimethylamino-1,3-phenylene, 5-trifluoromethyl-1,3-phenylene,5-acetamido-1,3-phenylene, 5-(2-hydroxyethylamino)-1,3-phenylene or5-cyanomethylamino-1,3-phenylene; or

Ar² is 3,5-pyridylene;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X isoxy, and which ring may bear a methyl or ethyl substituent alpha to X;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention comprises aheterocyclic derivative of the formula I wherein

Ar¹ is naphth-2-yl, 7-fluoronaphth-2-yl, 6,7-difluoronaphth-2-yl,7-methylnaphth-2-yl, 7-difluoromethylnaphth-2-yl, 5-bromonaphth-2-yl or5-trifluoromethylnaphth-2-yl;

A¹ is methylene;

Ar² is 1,3-phenylene, 5-fluoro-1,3-phenylene or5-trifluoromethyl-1,3-phenylene;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² -X-A³ - which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and X isoxy, and which ring may bear a methyl or ethyl substituent alpha to X;

or a pharmaceutically-acceptable salt thereof.

Specific especially preferred compounds of the invention include, forexample, the following heterocyclic derivatives of the formula I, orpharmaceutically-acceptable salts thereof:

4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,

3-methoxy-2-methyl-3-[3-(naphth-2-ylmethoxy)phenyl]tetrahydrofuran,

(2RS,4SR)-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxy-2-methyltetrahydropyran,

4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,

4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,

4-methoxy-4-[3-(3-phenylprop-2-ynyloxy)-5-trifluoromethylphenyl]tetrahydropyran,

4-[5-fluoro-3-(3-(4-fluorophenyl)prop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,

4-[5-(2-hydroxyethylamino)-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,

4-methoxy-4-[3-(3-phenylprop-2-ynyloxy)-5-ureidophenyl]tetrahydropyran,

4-[3-(3-(2-chlorophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran,

4-[5-fluoro-3-(3-(2-trifluoromethyl)phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,

4-[3-(3-(3,5-dichlorophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran,

4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxytetrahydropyran,

4-allyloxy-4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyran,

4-[3-(5-bromonaphth-2-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyran,

(2RS,4SR)-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran,

(2RS,4SR)-4-methoxy-2-methyl-4-[3-(7-methylnaphth-2-ylmethoxy)phenyl]tetrahydropyran,

(2RS,4SR)-4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxy-2-methyltetrahydropyran,

(2RS,4SR)-4-ethoxy-4-[3-(7-fluronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-2-methyltetrahydropyran,

(2RS,4SR)-4-[5-fluoro-3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran,

(2RS,4SR)-4-ethoxy-4-[5-fluoro-3-(7-fluoronaphth-2-ylmethoxy)phenyl]-2-methyltetrahydropyran,

(2RS,4SR)-4-allyloxy-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-2-methyltetrahydropyranand

(2RS,4SR)-4-allyloxy-2-ethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran.

A compound of the invention comprising a heterocyclic derivative of theformula I, or a pharmaceutically-acceptable salt thereof, may beprepared by any process known to be applicable to the preparation ofstructurally-related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which, unless otherwise stated, Ar¹, A¹, Ar²,R¹, R² and R³ have any of the meanings defined hereinbefore.

(a) The alkylation, in the presence of a suitable base, of a compound ofthe formula II with a compound of the formula Ar¹ -A¹ -Z wherein Z is adisplaceable group; provided that, when there is an amino, imino,alkylamino, hydroxy or carboxy group in Ar¹, Ar², R¹, R² or R³, anyamino, imino, alkylamino or carboxy group is protected by a conventionalprotecting group and any hydroxy group may be protected by aconventional protecting group or alternatively any hydroxy group neednot be protected;

whereafter any undesired protecting group in Ar¹, Ar², R¹, R² or R³ isremoved by conventional means.

A suitable displaceable group Z is, for example, a halogeno orsulphonyloxy group, for example a chloro, bromo, iodo,methanesulphonyloxy or toluene-p-sulphonyloxy group.

A suitable base for the alkylation reaction is, for example, an alkalior alkaline earth metal carbonate, hydroxide or hydride, for examplesodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, sodium hydride or potassium hydride. The alkylation reactionis preferably performed in a suitable inert solvent or diluent, forexample N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, andat a temperature in the range, for example, 10° to 150° C., convenientlyat or near ambient temperature.

A suitable protecting group for an amino, imino or alkylamino group is,for example, an acyl group for example a (1-4C)alkanoyl group(especially acetyl), a (1-4C)alkoxycarbonyl group (especiallymethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl), anarylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroylgroup (especially benzoyl). The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl oran aroyl group may be removed for example, by hydrolysis with a suitablebase such as an alkali metal hydroxide, for example lithium or sodiumhydroxide. Alternatively an acyl group such as a t-butoxycarbonyl groupmay be removed, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a (1-4C)alkyl group (especially methyl orethyl) or an arylmethyl group (especially benzyl). The deprotectionconditions for the above protecting groups necessarily vary with thechoice of protecting group. Thus, for example, an esterifying group suchas an alkyl or arylmethyl group may be removed, for example, byhydrolysis with a suitable base such as an alkali metal hydroxide, forexample lithium or sodium hydroxide. Alternatively an esterifying groupsuch as an arylmethyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example a (1-4C)alkanoyl group (especially acetyl), an aroylgroup (especially benzoyl) or an arylmethyl group (especially benzyl).The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

The starting materials of the formula II may be obtained by standardprocedures of organic chemistry. The preparation of examples of suchstarting materials is described within the accompanying non-limitingExamples which are provided for the purposes of illustration only. Othernecessary starting materials are obtainable by analogous procedures tothose described or by modifications thereto which are within theordinary skill of an organic chemist. The starting material of theformula II may be obtained, for example, by deprotecting a protectedether derivative of the formula III wherein R⁴ is a protecting group andAr², R¹, R² and R³ have the meanings defined hereinbefore.

A suitable protecting group R⁴ is, for example, an arylmethyl group(especially benzyl), a tri-(1-4C)alkylsilyl group (especiallytrimethylsilyl or t-butyldimethylsilyl), an aryldi-(1-4C)-alkylsilylgroup (especially dimethylphenylsilyl), a (1-4C)alkyl group (especiallymethyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) or atetrahydropyranyl group (especially tetrahydropyran-2-yl). Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.Alternatively a trialkylsilyl or an aryl dialkylsilyl group such as at-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, forexample, by treatment with a suitable acid such as hydrochloric,sulphuric, phosphoric or trifluoroacetic acid or with an alkali metal orammonium fluoride such as sodium fluoride or, preferably,tetrabutylammonium fluoride. Alternatively an alkyl group may beremoved, for example, by treatment with an alkali metal(1-4C)alkylsulphide such as sodium thioethoxide or, for example, bytreatment with an alkali metal diarylphosphide such as lithiumdiphenylphosphide. Alternatively a (1-4C)alkoxymethyl group ortetrahydropyranyl group may be removed, for example, by treatment with asuitable acid such as hydrochloric or trifluoroacetic acid.

The protecting group R⁴ may be, for example, a tri-(1-4C)-alkylsilylgroup which can be removed while the protecting group for any amino,imino, alkylamino, carboxy or hydroxy group in Ar², R¹, R² or R³ isretained.

The protected ether derivative of the formula III, wherein R⁴ has themeaning defined hereinbefore, may be obtained by the alkylation of thetertiary alcohol of the formula IV with an alkylating agent of theformula R¹ -Z, wherein Z is a displaceable group as definedhereinbefore, in the presence of a suitable base as definedhereinbefore, and provided that any amino, imino, alkylamino or hydroxygroup in Ar², R² or R³ is protected by a conventional protecting group.

The tertiary alcohol starting material of the formula IV may be obtainedby the reaction of a compound of the formula R⁴ -O-Ar² -Z, wherein R⁴and Ar² have the meanings defined hereinbefore and Z is a halogeno groupas defined hereinbefore and provided that any amino, alkylamino orhydroxy group in Ar² is protected with a conventional protecting group,with either an organometallic compound of the formula R⁶ -M, wherein R⁶is a (1-6C)alkyl group such as butyl and M is a metallic group, forexample lithium, to give an organometallic compound of the formula R⁴-O-Ar² -M, or with a metal such as magnesium to given an organometalliccompound of the formula R⁴ -O-Ar² -M-Z; whereafter either of theseorganometallic compounds may be reacted with a ketone of the formula R²-CO-R³, wherein R² and R³ have the meanings defined hereinbefore, andprovided that any imino or hydroxy group in R² and R³ is protected by aconventional protecting group.

(b) The alkylation, in the presence of a suitable base as definedhereinbefore, of a compound of the formula V with a compound of theformula R¹ -Z, wherein R¹ and Z have the meanings defined hereinbefore,provided that, when there is an amino, imino, alkylamino, hydroxy orcarboxy group in Ar¹, Ar², R² or R³, any amino, imino, alkylamino,hydroxy or carboxy group is protected by a conventional protectinggroup; whereafter any undesired protecting group in Ar¹, Ar², R² or R³is removed by conventional means.

The starting materials of the formula V may be obtained by standardprocedures of organic chemistry. The preparation of examples of suchstarting materials is described within the accompanying nonlimitingExamples which are provided for the purpose of illustration only. Othernecessary starting materials are obtainable by analogous procedures tothose described or by modifications thereto which are within theordinary skill of an organic chemist. The tertiary alcohol startingmaterial of the formula V may be obtained, for example, by thealkylation, in the presence of a suitable base, of a compound of theformula HO-Ar² -Z, wherein Ar² has the meaning defined hereinbefore andZ is a halogeno group as defined hereinbefore, with a compound of theformula Ar¹ -A¹ -Z, wherein Ar¹, A¹ and Z have the meanings definedhereinbefore, and provided that any amino, alkylamino, carboxy orhydroxy group in Ar¹ or Ar² is protected by a conventional protectinggroup, to give a compound of the formula Ar¹ -A¹ -O-Ar² -Z.Alternatively a compound of the formula Ar¹ -A¹ -O-Ar² -Z may beobtained, for example, by the alkylation, in the presence of a suitablebase, of a compound of the formula Ar¹ -A¹ -OH, wherein Ar¹ and A¹ havethe meanings defined hereinbefore, with a compound of the formula Z-Ar²-Z, wherein Z and Ar² have the meanings defined hereinbefore. Theproduct so obtained may be treated either with an organometalliccompound of the formula R⁶ -M, wherein R⁶ is a (1-6C)alkyl group such asbutyl and M is a metallic group, for example lithium, to give anorganometallic compound of the formula Ar¹ -A¹ -O-Ar² -M, or with ametal such as magnesium to give an organometallic compound of theformula Ar¹ -A¹ -O-Ar² -M-Z. Either of these organometallic compoundsmay be reacted with a ketone of the formula R² -CO-R³, provided that anyimino or hydroxy group in R² or R³ is protected by a conventionalprotecting group, to give the required tertiary alcohol startingmaterial of the formula V.

(c) For the production of those compounds of the formula I wherein A¹ isa (3-6C)alkynylene group, the coupling, in the presence of a suitableorganometallic catalyst, of a compound of the formula Ar¹ -Z wherein Ar¹has the meaning defined hereinbefore and Z is a halogeno group such asiodo, with an ethynyl compound of the formula VI, wherein A is(1-4C)alkylene and Ar², R¹, R² and R³ have the meanings definedhereinbefore.

A suitable organometallic catalyst is, for example, any agent known inthe art for such a coupling reaction. Thus, for example, a suitablereagent is formed when, for example, bis(triphenylphosphine)palladiumchloride or tetrakis(triphenylphosphine)palladium and a copper halide,for example curpous iodide, are mixed. The coupling is generally carriedout in suitable inert solvent or diluent, for example acetonitrile,1,2-dimethoxyethane, toluene or tetrahydrofuran, at a temperature in therange, for example, 10° to 80° C., conveniently at or near 50° C., andin the presence of a suitable base such as, for example, atri-(1-4C)alkylamine such as triethylamine, or a cyclic amine such aspiperidine.

The ethynyl compound of the formula VI, used as a starting material, maybe obtained, for example, by the alkylation, in the presence of asuitable base, of a compound of the formula II, wherein Ar², R¹, R² andR³ have the meanings defined hereinbefore, with an alkylating agent ofthe formula H--C.tbd.C--A--Z, wherein A has the meaning definedhereinbefore and Z is a halogeno group, and provided that any amino,imino, alkylamino, carboxy or hydroxy group in Ar², R¹, R² or R³ isprotected by a conventional protecting group.

(d) For the production of those compounds of the formula I wherein Ar¹or Ar² bears an alkylsulphinyl or alkylsulphonyl substituent, or whereinR² and R³ together form a group of the formula --A² -X-A³ - and X is asulphinyl or sulphonyl group, the oxidation of a compound of the formulaI wherein Ar¹ or Ar² bears an alkylthio substituent or wherein X is athio group.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or t-butyl methyl ether and at a temperature,for example, at or near ambient temperature, that is in the range 15 to35° C. When a compound carrying a sulphinyl group is required a milderoxidising agent may also be used, for example sodium or potassiummetaperiodate, conveniently in a polar solvent such as acetic acid orethanol. It will be appreciated that when a compound of the formula Icontaining a sulphonyl group is required, it may be obtained byoxidation of the corresponding sulphinyl compound as well as of thecorresponding thio compound.

(e) For the production of those compounds of the formula I wherein Ar¹or Ar² bears an alkanoylamino substituent, the acylation of a compoundof the formula I wherein Ar¹ or Ar² bears an amino substituent.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino; for example an acyl halide, forexample a (2-6C)alkanoyl chloride or bromide, in the presence of asuitable base, an alkanoic acid anhydride, for example a (2-6C)alkanoicacid anhydride, or an alkanoic acid mixed anhydride, for example themixed anhydride formed by the reaction of an alkanoic acid and a(1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonylchloride, in the presence of a suitable base. In general the reaction iscarried out in a suitable solvent or diluent such as methylene chloride,acetone, tetrahydrofuran or t-butyl methyl ether and at a temperature,for example, at or near ambient temperature, that is in the range 15° to35° C. A suitable base when it is required is, for example, pyridine,4-dimethylamino-pyridine, triethylamine, ethyldiisopropylamine,N-methylmorpholine, an alkali metal carbonate, for example potassiumcarbonate, or an alkali metal carboxylate, for example sodium acetate.

(f) For the production of those compounds of the formula I wherein R¹ isalkanoyl or benzoyl optionally bearing a substituent as definedhereinbefore, the acylation of a compound of the formula I wherein R¹ ishydrogen. For the production of those compounds of the formula I whereinR¹ is alkanoyl the acylation reaction may be carried out using, forexample, a suitable acylating agent as defined hereinbefore. For theproduction of those compounds of the formula I wherein R¹ is benzoyloptionally bearing a substituent the acylation may be carried out using,for example, a benzoyl halide, for example a benzoyl chloride orbromide, in the presence of a suitable base as defined hereinbefore.

(g) For the production of those compounds of the formula I wherein Ar¹bears an alkenyl substituent or A¹ is alkenylene, the reduction of thecorresponding compound wherein Ar¹ bears an alkynyl substituent or A¹ isalkynylene. In general conditions which are standard in the art for thereduction of an alkynyl or alkynylene group are used. Thus, for example,the reduction may be carried out by the hydrogenation of a solution ofthe alkynyl or alkynylene compound in an inert solvent or diluent in thepresence of a suitable metal catalyst. A suitable inert solvent is, forexample, an alcohol, for example methanol or ethanol, or an ether, forexample tetrahydrofuran or t-butyl methyl ether. A suitable metalcatalyst is, for example, palladium or platinum on an inert support, forexample charcoal or barium sulphate.

Preferably a palladium-on-barium sulphate catalyst is used tosubstantially prevent over-reduction of the alkynyl or alkynylene groupto an alkyl or alkylene group respectively. The reaction is generallycarried out at a temperature at or near ambient temperature, that is inthe range 15° to 35° C.

Alternatively the reduction may be carried out by treating a solution ofthe alkynyl or alkynylene compound in an inert solvent or diluent with asuitable mixture such as a 1:1 mixture of an organometallic hydride, forexample a di-(1-6C)alkylaluminium hydride such as diisobutylaluminiumhydride, and an alkyl metal, for example a (1-6C)alkyl lithium such asmethyl lithium. A suitable inert solvent or diluent is, for example,tetrahydrofuran, diethyl ether or t-butyl methyl ether and, in general,the reaction is carried out at a temperature, for example, in the range-25° C. to ambient temperature (especially -10° to 10° C).

(h) For the production of those compounds of the formula I wherein Ar²bears an alkoxy or substituted alkoxy substituent, or an alkylamino,dialkylamino or substituted alkylamino substituent, the alkylation of acompound of the formula I wherein Ar² bears a hydroxy substituent, or anamino substituent.

A suitable alkylating agent is, for example any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of amino to alkylamino, dialkylamino or substitutedalkylamino, for example an alkyl or substituted alkyl halide, forexample a (1-6C)alkyl chloride, bromide or iodide or a substituted(1-4C)alkyl chloride, bromide or iodide, in the presence of a suitablebase. A suitable base for the alkylation reaction is, for example, analkali or alkaline earth metal carbonate, hydroxide or hydride, forexample sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride. The alkylationreaction is preferably performed in a suitable inert solvent or diluent,for example N,N-dimethylformamide, dimethylsulphoxide, acetone,1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in therange, for example, 10° to 150° C., conveniently at or near ambienttemperature.

(i) For the production of those compounds of the formula I wherein Ar¹or Ar² bears an amino substituent, the reduction of a compound of theformula I wherein Ar¹ or Ar² bears a nitro substituent.

A suitable reducing agent is, for example, any agent known in the artfor the reduction of a nitro group to an amino group. Thus, for example,the reduction may be carried out by the hydrogenation of a solution ofthe nitro compound in an inert solvent or diluent in the presence of asuitable metal catalyst, for example finely divided platinum metal(obtained by the reduction of platinum oxide in situ). A suitable inertsolvent or diluent is, for example, an alcohol, for example methanol,ethanol or isopropanol, or an ether, for example tetrahydrofuran.

A further suitable reducing agent is, for example, an activated metalsuch as activated iron (produced by washing iron powder with a dilutesolution of an acid such as hydrochloric acid). Thus, for example, thereduction may be carried out by heating a mixture of the nitro compoundand the activated metal in a suitable solvent or diluent such as amixture of water and an alcohol, for example, methanol or ethanol, to atemperature in the range, for example, 50° to 150° C., conveniently ator near 70° C.

When a pharmaceutically-acceptable salt of a novel compound of theformula I is required, it may be obtained, for example, by reaction ofsaid compound with a suitable acid or base using a conventionalprocedure. When an optically active form of a compound of the formula Iis required, it may be obtained by carrying out one of the aforesaidprocedures using an optically active starting material, or by resolutionof a racemic form of said compound using a conventional procedure.

Many of the intermediates defined herein are novel, for example those ofthe formulae II, III, IV and V and these are provided as a furtherfeature of the invention.

As stated previously, the heterocyclic derivatives of the formula I areinhibitors of the enzyme 5-LO. The effects of this inhibition may bedemonstrated using one or more of the standard procedures set out below:

a) An in vitro spectrophotometric enzyme assay system, which assessesthe inhibitory properties of a test compound in a cell free system using5-LO isolated from guinea pig neutrophils and as described by D. Aharonyand R. L. Stein (J. Biol. Chem., 1986, 261(25), 11512-11519). This testprovides a measure of the intrinsic inhibitory properties againstsoluble 5-LO in an extracellular environment.

b) An in vitro assay system involving incubating a test compound withheparinised human blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using the specific radioimmunoassaydescribed by Carey and Forder (F. Carey and R. A. Forder, Brit. J.Pharmacol. 1985, 84, 34P) which involves the use of a protein-LTB₄conjugate produced using the procedure of Young et alia (Prostaglandins,1983, 26(4), 605-613). The effects of a test compound on the enzymecyclooxygenase (which is involved in the alternative metabolic pathwayfor arachidonic acid and gives rise to prostaglandins, thromboxanes andrelated metabolites) may be measured at the same time using the specificradioimmunoassay for thromboxane B₂ (TxB₂) described by Carey and Forder(see above). This test provides an indication of the effects of a testcompound against 5-LO and also cyclooxygenase in the presence of bloodcells and proteins. It permits the selectivity of the inhibitory effecton 5-LO or cyclooxygenase to be assessed.

c) An ex vivo assay system, which is a variation of test b) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and TxB₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

d) An in vitro assay system involving the measurement of the inhibitoryproperties of a test compound against the liberation of LTC₄ and PGE₂induced by zymosan on mouse resident peritoneal macrophages, using theprocedure of Humes (J. L. Humes et alia, Biochem. Pharmacol., 1983, 32,2319-2322) and conventional radioimmunoassay sistems to meassur LTC₄ andPGE₂. This test provides an indication of inhibitory effects against5-LO and cyclooxygenase in a non-proteinaceous system.

e) An in vivo system involving the measurement of the effects of a testcompound in inhibiting the inflammatory response to arachidonic acid inthe rabbit skin model developed by D. Aked et alia (Brit. J. Pharmacol.,1986, 89, 431-438). This test provides an in vivo model for 5-LOinhibitors administered topically or orally.

f) An in vivo system involving measuring the effects of a test compoundadministered orally or intravenously on a leukotriene dependentbronchoconstriction induced by an antigen challenge in guinea pigspre-dosed with an antihistamine (mepyramine), a β-adrenergic blockingagent (propranolol) and a cyclooxygenase inhibitor (indomethacin), usingthe procedure of W. H. Anderson et alia (British J Pharmacology, 1983,78(1), 67-574). This test provides a further in vivo test for detecting5-LO inhibitors.

Although the pharmacological properties of the compounds of the formulaI vary with structural changes as expected, in general compounds of theformula I possess 5-LO inhibitory effects at the followingconcentrations or doses in one or more of the above tests a)-f):

Test a): IC₅₀ in the range, for example, 0.01-30 μM;

Test b): IC₅₀ (LTB₄) in the range, for example, 0.01-40 μM IC₅₀ (TxB₂)in the range, for example, 40-200 μM;

Test c): oral ED₅₀ (LTB₄) in the range, for example, 1-200 mg/kg;

Test d): IC₅₀ (LTC₄) in the range, for example, 0.001-1 μM, IC₅₀ (PGE₂)in the range, for example, 20-1000 μM;

Test e): inhibition of inflammation in the range, for example, 0.3-100μg intradermally;

Test f): ED₅₀ in the range, for example, 0.5-10 mg/kg i.v.

No overt toxicity or other untoward effects are present in tests c), e)and/or f) when compounds of the formula I are administered at severalmultiples of their minimum inhibitory dose or concentration.

Thus, by way of example, the compound4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran has an IC₅₀ of0.1 μM against LTB₄ and of >40 μM against TxB₂ in test b), and an oralED₅₀ of 5 mg/kg against LTB₄ in test c). In general those compounds ofthe formula I which are particularly preferred have an IC₅₀ of <1 μMagainst LTB₄ and >40 μM against TxB₂ in test b), and an oral ED₅₀ of<100 mg/kg against LTB₄ in test c).

These compounds are examples of heterocyclic derivatives of theinvention which show selective inhibitory properties for 5-LO as opposedto cyclooxygenase, which selective properties are expected to impartimproved therapeutic properties, for example, a reduction in or freedomfrom the gastrointestinal side-effects frequently associated withcyclooxygenase inhibitors such as indomethacin.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a heterocyclic derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof, inassociation with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powderor a liquid aerosol; for sub-lingual or buccal use, for example a tabletor capsule; or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The amount of active ingredient (that is a heterocyclic derivative ofthe formula I or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided aheterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of aheterocyclic derivative of the formula I will naturally vary accordingto the nature and severity of the conditions, the age and sex of theanimal or patient and the route of administration, according to wellknown principles of medicine. As mentioned above, heterocyclicderivatives of the formula I are useful in treating those allergic andinflammatory conditions which are due alone or in part to the effects ofthe metabolites of arachidonic acid arising by the linear (5-LOcatalysed) pathway and in particular the leukotrienes, the production ofwhich is mediated by 5-LO. As previously mentioned, such conditionsinclude, for example, asthmatic conditions, allergic reactions, allergicrhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascularand cerebrovascular disorders of an inflammatory nature, arthritic andinflammatory joint disease, and inflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, the compounds ofthe formula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylicacid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises a heterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof as defined hereinbefore, in conjunction or admixture with acyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such asmentioned above), and a pharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of the compounds of the formula I may bedemonstrated, for example in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The compounds of the formula I may also be used in combination withleukotriene antagonists such as those disclosed in European PatentSpecification Nos. 179619, 199543, 220066, 227241, 242167, 290145,337765, 337766 and 337767, which are incorporated herein by way ofreference.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporations in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-20° and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) obtained from E. Meck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I have satisfactory microanalysesand their structures were confirmed by NMR and mass spectral techniques;

(vi) intermediates were not generally full characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus; melting points for theend-products of the formula I were determined after recrystallisationfrom a conventional organic solvent such as ethanol, methanol, acetone,ether or hexane, alone or in admixture; and

(viii) the specific rotation, [α]^(t), of plane polarised light wasdetermined using the sodium D line (5890 Angstroms), at 20° C., andgenerally using sample concentrations of approximately 1 g/100 ml ofsolvent.

EXAMPLE 1

A mixture of 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]-tetrahydropyran(1.9 g), sodium hydride (0.27 g of a 50% w/w dispersion in mineral oil),1,4,7,10,13-pentaoxacyclopentadecane (hereinafter 15-crown-5, 0.2 g) andtetrahydrofuran (10 ml) was stirred at ambient temperature for 15minutes. Methyl iodide (0.35 ml) was added and the mixture was stirredat ambient temperature for 15 hours. The mixture was evaporated and theresidue was partitioned between diethyl ether and water. The organiclayer was separated, washed with a saturated aqueous sodium chloridesolution, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 9:1 v/v mixture of methylene chloride anddiethyl ether as eluent. There was thus obtained4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (1.8 g, 94%),m.p. 66.5°-67.5° C.

The 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran startingmaterial was obtained as follows:

A Grignard reagent was prepared by heating a mixture of3-(naphth-2-ylmethoxy)bromobenzene (3 g), magnesium powder (0.23 g) andtetrahydrofuran (12 ml) to 30° C. for 1.5 hours. The reagent was cooledto 20° C. and a solution of tetrahydropyran-4-one (0.88 ml) intetrahydrofuran (5 ml) was added dropwise. The mixture was heated to 30°C. for 15 hours, evaporated and the residue was partitioned betweenethyl acetate and water. The organic layer was separated, washed with asaturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a7:3 v/v mixture of methylene chloride and diethyl ether as eluent. Therewas thus obtained4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]-tetrahydropyran (2.06 g,42%), m.p. 130°-131° C.

EXAMPLE 2

The procedure described in Example 1 was repeated except that theappropriate cyclic ether was used in place of4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran. There werethus obtained the compounds described in the following table:

                  TABLE IA                                                        ______________________________________                                         ##STR2##                                                                     Example 2:-                                                                   Compound                                Yield                                 No.      A.sup.2  X     A.sup.3 m.p. (°C.)                                                                     (%)                                   ______________________________________                                        1        CH.sub.2 O     (CH.sub.2).sub.2                                                                      89-90   37                                    2        (CH.sub.2).sub.2                                                                       O     CH(Me)  106-107 70                                    3        (CH.sub.2).sub.2                                                                       S     (CH.sub.2).sub.2                                                                      106-107 57                                    .sup. 4.sup.a                                                                          CH.sub.2 O     (CH.sub.2).sub.4                                                                      oil     58                                    5        CH.sub.2 O     (CH.sub.2).sub.3                                                                      79-80   47                                    ______________________________________                                    

NOTES

a. The product displayed the following characteristic NMR signals(CDCl₃, & values):- 1.6-2.25(m, 6H), 3.05(s, 3H), 3.5-4.15(m, 4H),5.23(s, 2H), 6.8-7.7(m, 7H), 7.7-7.8(m, 4H).

The appropriate cyclic ether starting materials were obtained using theprocedure described in the portion of Example 1 which is concerned withthe preparation of starting materials except that the appropriatealdehyde or ketone was used in place of tetrahydropyran-4-one. Therewere thus obtained the cyclic ether starting materials described in thefollowing table:

                  TABLE IB                                                        ______________________________________                                         ##STR3##                                                                     Starting Material                                                             for Example 2:-                   m.p.   Yield                                Compound No.                                                                             A.sup.2  X     A.sup.3 (°C.)                                                                         (%)                                  ______________________________________                                         1a        CH.sub.2 O     (CH.sub.2).sub.2                                                                      89-90  65                                   2          (CH.sub.2).sub.2                                                                       O     CH(Me)  100-101                                                                              30                                   3          (CH.sub.2).sub.2                                                                       S     (CH.sub.2).sub.2                                                                      140-141                                                                              59                                   .sup. 4.sup.b                                                                            CH.sub.2 O     (CH.sub.2).sub.4                                                                      115-116                                                                              30                                   .sup. 5.sup.c                                                                            CH.sub.2 O     (CH.sub.2).sub.3                                                                      oil    46                                   ______________________________________                                    

NOTES

a. 3-Ketotetrahydrofuran, used as a starting material, was obtained bySwern oxidation of 3-hydroxytetrahydrofuran using the proceduredescribed in J. Org. Chem., 1978, 43, 2480.

b. 3-Ketooxepane (0.17 g; 26%), used as a starting material, wasobtained by hydrogenation of a solution of 2,3,4,5-tetrahydrooxepin-3-ol(0.6 g; Chem & Ind., 1985, 600) in ethanol (30 ml) in the presence of 5%palladium-on-charcoal catalyst; followed by Swern oxidation of theresulting 3-hydroxyoxepane using the procedure described in J. Org.Chem., 1978, 43, 2480.

c. 3-Ketotetrahydropyran, used as a starting material, was obtained bySwern oxidation of 3-hydroxytetrahydropyran (J. Org. Chem., 1985, 50,1587) using the procedure described in J. Org. Chem., 1978, 43, 2480.

EXAMPLE 3

A mixture of (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran(0.45 g) and dimethylformamide (5 ml) cooled in an ice bath, sodiumhydride (0.068 g of a 55% w/w dispersion in mineral oil) was added andthe mixture was stirred for 45 minutes. Methyl iodide (0.11 ml) wasadded and the mixture was stirred for 15 minutes. The ice bath wasremoved and the mixture was stirred at ambient temperature for 30minutes. The mixture was poured into water (15 ml) and extracted withethyl acetate (3×15 ml). The combined organic extracts were washed witha saturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a10:1 v/v mixture of toluene and ethyl acetate as eluent. There was thusobtained as an oil, (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran(0.33 g, 71%);

NMR Spectrum (CDCl₃ ; δ values) 1.18 (d, 3H), 1.52 (doublet of doublets,1H), 1.86-1.98 (m, 3H), 2.97 (s, 3H), 3.8-3.95 (m, 3H), 5.05 (s, 2H),6.60 (doublet of triplets, 1H), 6.70 (doublet of triplets, 1H), 6.80 (t,1H), 7.3-7.44 (m, 5H);

Mass Spectrum P m/e 330;

Elemental Analysis Found C, 72.5; H, 7.1; C₂₀ H₂₃ FO₃ requires C, 72.7;H, 7.0%.

The (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyranstarting material was obtained as follows:

A mixture of benzyl alcohol (10 g), sodium hydride (4.44 g of a 50% w/wdispersion in meneral oil) and dimethylacetamide (180 ml) was stirred atambient temperature for 1 hour; 1-bromo-3,5-difluorobenzene (10.65 ml)was added and the exothermic reaction mixture was stirred for 2 hours.The mixture was evaporated and the residue was partitioned betweenmethylene chloride and water. The organic layer was separated, washedwith water, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 20:1 v/v mixture of petroleum ether (b.p.60°-80° C.) and ethyl acetate as eluent. There was thus obtained, as aliquid, benzyl 3-bromo-5-fluorophenyl ether (19.5 g, 75%).

A solution of n-butyl-lithium (6.5 ml of a 1.6 M solution in hexane) wasadded to a solution of a portion (2.81 g) of the benzyl ether soobtained in tetrahydrofuran (50 ml) which had been cooled to -78° C. andthe mixture was stirred at this temperature for 40 minutes. A solutionof 2-methyltetrahydropyran-4-one (1.14 g; J. Amer. Chem. Soc., 1982,4666) in tetrahydrofuran (5ml) was added, the mixture was stirred at-78° C. for 30 minutes, and then allowed to warm to ambient temperature.A saturated aqueous ammonium chloride solution (30 ml) was added and themixture was extracted with ethyl acetate (3×30 ml). The organic extractswere combined, washed with a saturated aqueous sodium chloride solution,dried (MgSO₄) and evaporated. The residue, containing a mixture ofdiastereoisomers, was purified and the isomers were separated by columchromatography using a 5:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran(0.74 g, 24%) as an oil, i.e. the 2-methyl and 4-hydroxy substituentsare in trans relationship;

NMR Spectrum (CDCl₃, δ values) 1.20 (d, 3H), 1.58 (broad s, 1H, OH),1.52 (s, 2H), 1.99-2.14 (m, 1H), 3.86-4.02 (m, 3H), 5.05 (s, 2H), 6.60(doublet of triplets, 1H), 6.80 (doublet of triplets, 1H), 6.90 (s, 1H),7.28-7.48 (m, 5H, aromatic); and (2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran(1.52 g, 48%), m.p. 82°-83° C., i.e. the 2-methyl and 4-hydroxysubstituents are in a cis relationship;

NMR Spectrum (CDCl₃, δ values) 1.21 (t, 3H), 1.66 (doublet of doublets,1H), 1.80 (broad s, 1H), 1.96 (triplet of doublets, 1H), 2.23-2.35 (m,2H), 3.30-3.42 (m, 2H), 3.94 (doublet of quartets, 1H), 5.05 (s, 2H),6.64 (doublet of triplets, 1H), 6.79 (doublet of triplets, 1H), 6.87 (s,1H), 7.30-7.42 (m, 5H, aromatic).

EXAMPLE 4

The procedure described in Example 3 was repeated except that the otherdiasteroisomer described in the portion of Example 18 which is concernedwith the preparation of starting materials, namely (2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyranwas used as a starting material. There was thus obtained (2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran,as an oil (75%);

NMR Spectrum (CDCl₃, δ values) 1.20 (d, 3H), 1.60 (doublet of doublets,1H), 1.91 (triplet of doublets, 1H), 2.22-2.32 (m, 2H), 2.88 (s, 3H),3.3-3.43 (m, 2H), 3.9-4.14 (m, 1H), 5.06 (s, 2H), 6.65 (doublet oftriplets, 1H), 6.74 (doublet of triplets, 1H), 6.81 (t, 1H), 7.3-7.44(m, 5H);

Mass Spectrum P m/e 330;

Elemental Analysis Found C, 72.6; H, 7.1; C₂₀ H₂₃ FO₃ requires C, 72.7;H, 7.0%.

EXAMPLE 5

A mixture of (2RS,4SR)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran(0.35 g), 3-phenylprop-2-ynyl bromide (0.315 g), potassium carbonate(0.3 g) and dimethylformamide (5 ml) was stirred at ambient temperaturefor 15 hours. The mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 97.5: 2.5 v/v mixture oftoluene and ethyl acetate as eluent. There was thus obtained (2RS,4SR)-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxy-2-methyltetrahydropyran(0.37 g, 72%), as an oil;

NMR Spectrum (CDCl₃, δ values) 1.19 (d, 3H), 1.55 (doublet of doublets,1H), 1.87-2.02 (m, 5H), 3.0 (s, 3H), 3.8-3.95 (m, 3H), 4.92 (s, 2H),6.64-6.78 (m, 2H), 6.88 (s, 1H), 7.24-7.98 (m, 5H);

Mass Spectrum P m/e 354;

Elemental Analysis Found, C, 72.0; H, 6.2; C₂₂ H₂₃ FO₃. 0.5 EtOAcrequires C, 72.3; H, 6.8%.

The (2RS,4SR)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran usedas a starting material was obtained as follows:

A mixture of (2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran(1.58 g; Ex. 3), 10% palladiumon-charcoal catalyst (0.16 g) and ethanol(30 ml) was stirred under an atmosphere of hydrogen for 4 hours. Themixture was filtered and the filtrate was evaporated. There was thusobtained the required starting material (1 g, 87%), m.p. 127° C.

EXAMPLE 6

The procedure described in Example 5 was repeated except that the otherdiasteroisomer, namely (2SR,4SR)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran, wasused as a starting material. There was thus obtained (2SR,4SR)-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxy-2-methyltetrahydropyranas an oil (78%);

NMR Spectrum (CDCl₃, δ values) 1.18 (d, 3H), 1.62 (doublet of doublets,1H), 1.93 (triplet of doublets, 1H), 2.3 (m, 2H), 2.90 (s, 3H), 3.4 (m,2H), 3.96 (doublet of quartets, 1H), 4.93 (s, 2H), 6.68-6.83 (m, 2H),6.91 (s, 1H), 7.25-7.48 (m, 5H);

Mass Spectrum P m/e 354;

Elemental Analysis Found C, 72.6; H, 6.3; C₂₂ H₂₃ FO₃. 0.33 EtOAcrequires C, 73.0; H, 6.7%.

The (2SR,4SR)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran usedas a starting material was obtained using the hydrogenolysis proceduredescribed in the portion of Example 5 which is concerned with thepreparation of starting materials provided that the appropriatediastereoisomer (Ex. 4) was selected. There was thus obtained therequired starting material (95%), m.p. 116° C.

EXAMPLE 7

The procedure described in Example 5 was repeated using the appropriatealkylating agent and the appropriate phenol. There was thus obtained thecompounds described in the following table:

                  TABLE II                                                        ______________________________________                                         ##STR4##                                                                     Ex. 7                                                                         Compd.                              m.p. Yield                                No.    Ar.sup.1A.sup.1                                                                             R.sup.1                                                                              R       (°C.)                                                                       (%)                                  ______________________________________                                    

NOTES

a. The product displayed the following character NMR signals (CDCl₃,delta values): 2.0(m, 4H), 2.98(s, 3H), 3.82(m, 4H), 4.92(s, 2H),7.0-7.4(m, 9H).

The 4-(3-hydroxyphenyl)-4-methoxytetrahydropyran used as a startingmaterial was obtained as follows:-3-Methoxymethoxyphenyl bromide wasprepared by the reaction of 3-bromophenol and dimethoxymethane using thegeneral procedure described in Synthesis, 1976, 244. A Grignard reagentwas prepared by heating a mixture of 3-methoxymethoxyphenyl bromide (6g), magnesium (0.66 g) and tetrahydrofuran (34 ml) to 30° C. for 2hours. The reagent was cooled to ambient temperature and a solution oftetrahydropyran-4-one (2.76 g) in tetrahydrofuran (2 ml) was addeddropwise. The mixture was stirred at ambient temperature for 15 hoursand evaporated. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 9:1 v/v mixture of methylenechloride and diethyl ether as eluent. There was thus obtained4-hydroxy-4-(3-methoxymethoxyphenyl)tetrahydropyran (4.5 g, 69%), as anoil.

A mixture of a portion (2 g) of the product so obtained, sodium hydride(55% w/w dispersion in mineral oil, 0.74 g) and tetrahydrofuran (50 ml)was stirred at ambient temperature for 15 minutes. Methyl iodide (1.42ml) and 15-crown-5 (0.1 g) were added and the mixture was stirred atambient temperature for 15 hours. The mixture was evaporated and theresidue was partitioned between methylene chloride and water. Theorganic layer was separated, washed with water, dried (MgSO₄) andevaporated. There was thus obtained4-methoxy-4-(3-methoxymethoxyphenyl)tetrahydropyran (2.1 g, 98%), as anoil.

A mixture of the product so obtained, concentrated hydrochloric acid(0.8 ml), isopropanol (3.5 ml) and tetrahydrofuran (15 ml) was stirredat ambient temperature for 24 hours. The mixture was evaporated and theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with a saturated aqueous sodium chloride solution,dried (MgSO₄) and evaporated. There was thus obtained4-(3-hydroxyphenyl)-4-methoxytetrahydropyran (1.54 g, 93%), as acolourless oil, which was used without further purification.

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.75-2.0(m, 1H), 2.3-2.75(m, 1H), 2.93(s, 3H),2.94(s, 3H), 3.0-3.91(m, 5H), 4.91(s, 2H), 6.85-7.6(m, 9H). The 3- and4-methoxy groups were in a trans-relationship.

The (3RS, 4SR)-4-(3-hydroxyphenyl)-3,4-dimethoxytetrahydropyran used asa starting material was obtained as follows:

A mixture of 4-hydroxy-4-(3methoxymethoxyphenyl)tetrahydropyran (2 g),5-angstrom molecular sieves (20 g) and toluene (20 ml) was heated to 80°C. for 5 hours. The mixture was filtered and the residue was washed insuccession with toluene and acetone. The combined filtrate and washingswere combined and evaporated. The residue was purified by columnchromatography using a 19:1 v/v mixture of methylene chloride anddiethyl ether as eluent. There was thus obtained2,3-dihydro-4-(3-methoxymethoxyphenyl)-6H-pyran (1.3 g, 70%), as an oil.

m-Chloroperbenzoic acid (1.53 g) was added to a stirred suspension ofthe product so obtained (1.3 g), sodium bicarbonate (0.75 g) andmethylene chloride (15 ml) which had been cooled to 0° C., and themixture was stirred at 0° C. for 1 hour and then at ambient temperaturefor 15 hours. The mixture was filtered and the residue was washed withmethylene chloride. The combined filtrate and washings were washed withdilute aqueous sodium hydroxide solution, and with water, dried (MgSO₄)and evaporated. The epoxide (1.2 g, 92%) so obtained was used withoutfurther purification.

The procedure described in Tet. Let., 1968, 24, 1755 was used to reactthe epoxide (1.2 g) obtained above with sodium hydroxide. The product soobtained was purified by column chromatography using a 3:2 v/v mixtureof methylene chloride and diethyl ether as eluent. There was thusobtained (3RS, 4SR)-3,4-dihydroxy-4-(3-methoxymethoxyphenyl)tetrahydropyran (0.7 g, 65%) as an oil; the 3-and 4-hydroxy groups beingin a trans-relationship.

The product so obtained was reacted with methyl iodide (4 equivalents)in the presence of sodium hydride (2.5 equivalents) using the proceduredescribed in Example 1. There was thus obtained (3RS,4SR)-3,4-dimethoxy-4-(3-methoxymethoxyphenyl)tetrahydropyran (0.58 g,77%) as an oil.

The product so obtained was reacted with hydrochloric acid using theprocedure described in the third paragraph of the portion of Note a.There was thus obtained the required starting material (0.44 g, 92%),m.p. 146°-148° C.

c. The (3RS,4SR)-3-hydroxy-4-(3-hydroxyphenyl)-4-methoxymethoxytetrahydropyran usedas a starting material was obtained as follows:

The procedure described in the first paragraph of the portion of Note a.above which is concerned with the preparation of starting materials wasrepeated, except that 3-benzyloxyphenyl bromide was used in place of3-methoxymethoxyphenyl bromide. The product so obtained was dehydratedusing the procedure described in the first paragraph of the portion ofNote b. above which is concerned with the preparation of startingmaterials. There was thus obtained4-(3-benzyloxyphenyl)-2,3-dihydro-6H-pyran which was oxidised and theepoxide so obtained was reacted with sodium hydroxide using theprocedures described in the second and third paragraphs of the portionof Note b. above which is concerned with the preparation of startingmaterials. There was thus obtained (3RS,4SR)-4-(3-benzyloxyphenyl)-3,4-dihydroxytetrahydropyran in an overallyield of 42%, as an oil, the 3- and 4-hydroxy groups being in atrans-relationship.

A mixture of the product so obtained (1.76 g), imidazole (2 g),tert-butyldimethylsilyl chloride (2.26 g) and dimethylformamide (6 ml)was stirred at ambient temperature for 15 hours. The mixture waspartitioned between diethyl ether and water. The organic layer waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 9:1 v/v mixture of methylenechloride and diethyl ether as eluent. There was thus obtained (3RS,4SR)-4-(3-benzyloxyphenyl)-3-(tert-butyldimethylsilyloxy)-4-hydroxytetrahyropyran(1.9 g, 78%), m.p. 90°-92° C.

The product so obtained was methylated using the procedure described inExample 1. There was thus obtained (3RS,4SR)-4-(3-benzyloxyphenyl)-3-(tert-butyldimethylsilyloxy)-4-methoxytetrahydropyran(1.69 g, 89%), as an oil.

Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 16 ml) was addedto a mixture of the compound so otained and tetrahydrofuran (32 ml) andthe mixture was stirred at ambient temperature for 15 hours. The mixturewas evaporated and the residue was partitioned between diethyl ether andwater. The organic phase was dried (MgSO₄) and evaporated. The residuewas purified by column chromatography using a 9:1 v/v mixture ofmethylene chloride and diethyl ether as eluent. There was thus obtained(3RS, 4SR)-4-methoxytetrahydropyran (1.06 g, 86%), m.p. 85°-86° C.

A mixture of the product so obtained, 10% palladium-on-charcoal catalyst(0.1 g) and ethanol (20 ml) was stirred at ambient temperature under anatmosphere of hydrogen for 15 hours. The mixture was filtered andevaporated and there was thus obtained the required starting material(0.7 g, 92%), m.p. 159°-160° C.

d. The (3SR, 4SR)-4-(3-hydroxyphenyl)-3,4-dimethoxytetrahydropyran usedas a starting material was obtained as follows:

4-(3-Benzyloxyphenyl)-2,3-dihydro-6H-pyran, obtained as described inNote c. above, was oxidised using the procedure described in the secondparagraph of the portion of Note b. above which is concerned with thepreparation of starting materials. The epoxide (1 g) so produced wascleaved, using the procedure described in J. Org. Chem., 1979, 44 1646,to give (3SR, 4SR)-4-(3-benzyloxyphenyl)-3,4-dihydroxytetrahydropyran(1.06 g, 98%) which was used without further purification.

A portion (0.5 g) of the product so obtained was reacted with methyliodide (4 equivalents) in the presence of sodium hydride (2.5equivalents) using the procedure described in Example 1. The product soobtained was treated with hydrogen in the presence of palladium usingthe procedure described in the last paragraph of Note c. above. Therewas thus obtained the required starting material (0.3 g, 67%), m.p.155°-156° C.

EXAMPLE 8

The procedure described in Example 5 was repeated using the appropriatealkylating agent and the appropriate phenol. There was thus obtained thecompounds described in the following table:

                  TABLE III                                                       ______________________________________                                         ##STR5##                                                                     Ex. 8                                                                         Compd.                             m.p.  Yield                                No.    Ar.sup.1A.sup.1                                                                           Ar.sup.2   R.sup.1                                                                            (°C.)                                                                        (%)                                  ______________________________________                                        1.sup.a                                                                              7-fluoronaphth-                                                                           1,3-phenylene                                                                            Me   48-50 90                                          2-ylmethyl                                                             2.sup.b                                                                              7-methylnaphth-                                                                           1,3-phenylene                                                                            Me   96-97 96                                          2-ylmethyl                                                             3.sup.c                                                                              7-methylnaphth-                                                                           5-fluoro-1,3-                                                                            Et   oil   74                                          2-ylmethyl  phenylene                                                  4.sup.d                                                                              7-fluoronaphth-                                                                           5-fluoro-1,3-                                                                            Et   oil   86                                          2-ylmethyl  phenylene                                                  5.sup.e                                                                              3-phenylprop-                                                                             1,3-phenylene                                                                            Me   oil   87                                          2-ynyl                                                                 ______________________________________                                    

NOTES

a. The (2RS,3SR)-3-(3-hydroxyphenyl)-3-methoxy-2-methyltetrahydrofuranused as a starting material was obtained as follows:

The procedures described in Note a. of Example 7 were repeated exceptthat 2-methyltetrahydrofuran-3-one was used in place oftetrahydropyran-4-one. There was thus obtained the required startingmaterial in 54% yield, m.p. 170°-171° C.; the 2-methyl and 3-methoxygroups being in a cis-relationship.

The 2-bromomethyl-7-fluoronaphthalene used as starting material wasobtained as described in the Notes below Table IV within Example 15below.

b. The 2-bromomethyl-7-methylnaphthalene used as starting material wasobtained from 2,7-dimethylnaphthalene using the methods described in theNotes below Table IV within Example 15 below.

c. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.09(t, 3H), 1.25(s, 3H), 2.57(m, 2H), 2.59(s,3H), 3.0-4.14(m, 5H), 5.19(s, 2H), 6.5-7.9(m, 9H).

The(2RS,3SR)-3-ethoxy-3-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydrofuranused as a starting material was obtained as follows:

A Grignard reagent was prepared by heating a mixture of3-benzyloxy-5-fluorophenyl bromide (4.2 g), magnesium powder (0.365 g)and tetrahydrofuran (20 ml) to 40° C. for 1 hour. The reagent was cooledto ambient temperature and 2-methyltetrahydrofuran-3-one (1.16 ml) wasadded dropwise. The mixture was stirred at ambient temperature for 3hours and then partitioned between ethyl acetate and water. The organiclayer was washed with water, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography using a 19:1 v/v mixture ofmethylene chloride and diethyl ether as eluent. There was thus obtained(2RS,3SR)-3-(3-benzyloxy-5-fluorophenyl)-3-hydroxy-2-methyltetrahydrofuran(2.3 g, 64%), m.p. 83°-84° C.; the 2-methyl and 3-hydroxy groups beingin a cis-relationship. A portion (1.1 g) of the product so obtained wasreacted with ethyl iodide using the procedure described in Example 1.There was thus obtained (2RS,3SR)-3-(3-benzyloxy-5-fluorophenyl)-3-ethoxy-2-methyltetrahydrofuran (0.82 g,68%), as an oil.

A mixture of the product so obtained, 10% palladium-on-charcoal (0.1 g)and ethanol (5 ml) was stirred at ambient temperature under anatmosphere of hydrogen for 4 hours. The mixture was filtered andevaporated. There was thus obtained the required starting material (0.54g, 92%), m.p. 136°-137° C.

d. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.09-1.25(2 t's, 6H), 2.43(t, 2H), 3.0-4.2(m, 5H),5.20(s, 2H), 6.5-7.98(m, 9H).

e. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 2.35-2.6(m, 2H), 3.17(s, 3H), 3.72(q,1H), 3.9-4.25(m, 2H), 4.93(s, 2H), 6.8-7.5(m, 9H).

EXAMPLE 9

The procedure described in Example 1 was repeated except that allylbromide was used in place of methyl iodide and dimethylformamide wasused in place of tetrahydrofuran. There was thus obtained4-allyloxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (57%), as anoil.

NMR Spectrum (CDCl₃, delta values) 1.8-2.2(m, 4H), 3.5-3.65(m, 2H),3.75-4.1(m, 4H), 5.0-5.4(m, 4H), 5.6-6.1(m, 1H), 6.8-8.0(m, 11H).

EXAMPLE 10

The procedure described in Example 1 was repeated except that ethyliodide was used in place of methyl iodide and dimethylformamide was usedin place of tetrahydrofuran. There was thus obtained4-ethoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (60%), as anoil.

NMR Spectrum (CDCl₃, delta values) 1.1(t, 3H), 1.96(m, 4H), 3.07(q, 2H),3.8(m, 4H), 5.23(s, 2H), 6.8-7.9(m, 11H).

EXAMPLE 11

Using the procedure described in Example 1,(3RS,4SR)-3-hydroxy-4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran[Example 7, Compound No. 3] was reacted with methyl iodide to give(3RS,4SR)-3,4-dimethoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran(90%), m.p. 131°-133° C.

The reaction described immediately above was repeated except thatpropargyl bromide was used in place of methyl iodide. There was thusobtained(3RS,4SR)-4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]-3-(prop-2-ynyloxy)tetrahydropyran(62%), m.p. 86°-88° C.

EXAMPLE 12

Using the procedure described in Example 1,4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane was reacted withmethyl iodide to give 4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane(36%), m.p. 69°-70° C.

The reaction described immediately above was repeated except that allylbromide was used in place of methyl iodide and dimethylformamide wasused as the reaction solvent. There was thus obtained4-allyloxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane (25%), m.p. 57°-58°C.

The 4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]oxepane used as a startingmaterial was obtained using the procedure described in the portion ofExample 1 which is concerned with the preparation of starting materialsexcept that 4-ketooxepane (Chem. Ber., 1958, 91, 1589) was used in placeof tetrahydropyran-4-one.

EXAMPLE 13

A solution of n-butyl-lithium (0.625 ml of a 1.6M solution in hexane)was added dropwise to a solution of2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]propane-1,3-diol andtetrahydrofuran which had been cooled to 0° C. A solution ofp-toluenesulphonyl chloride (0.19 g) in tetrahydrofuran (1 ml) was addedand the mixture was stirred at 0° C. for 30 minutes.

A solution of n-butyl-lithium (0.625 ml, 1.6M) was added and the mixturewas heated to 60° C. for 4 hours. The mixture was evaporated and theresidue was partitioned between diethyl ether and water. The organiclayer was separated, washed with water, dried (MgSO₄) and evaporated.The residue was purified by column chromatography using a 5:1 v/vmixture of methylene chloride and diethyl ether as eluent. There wasthus obtained 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]oxetane (0.072g, 22%), m.p. 71°-72° C.

The 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]propane-1,3-diol used as astarting material was obtained as follows:

A Grignard reagent was prepared by heating a mixture of3-benzyloxyphenyl bromide (2.55 g), magnesium powder (0.232 g) andtetrahydrofuran (20 ml) to 60° C. for 1 hour. A solution ofbenzyloxyacetonitrile (1.36 g) in tetrahydrofuran (1 ml) was addeddropwise and the mixture was heated to 60° C. for 60 minutes. Themixture was acidified by the addition of 1N hydrochloric acid solution(50 ml) and extracted with diethyl ether. The organic layer was washedwith water and with a saturated aqueous sodium chloride solution, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using methylene chloride as eluent. There was thusobtained benzyloxymethyl 3-(naphth-2-ylmethoxy)phenyl ketone (2.11 g,65%) as an oil.

A solution of this product (2.1 g) in tetrahydrofuran (3 ml) was addeddropwise to a solution of isopropoxydimethylsilymethylmagnesium chloride[prepared as described in J. Org. Chem., 1983, 48, 2120, fromchloromethylisopropoxydimethylsilane (1.88 g) and magnesium powder (0.27g) in tetrahydrofuran (15 ml)]. The mixture was stirred at ambienttemperature for 1 hour, washed with a saturated aqueous solution ofammonium chloride and then with a saturated aqueous solution of sodiumchloride. The organic layer was separated, dried (Na₂ SO₄) andevaporated to give3-benzyloxy-2-(3-benzyloxyphenyl)-1-isopropoxydimethylsilylpropan-2-ol,as a yellow oil.

A mixture of the product so obtained, sodium bicarbonate (0.58 g),hydrogen peroxide (3 ml, 30% w/v in water), methanol (10 ml) andtetrahydrofuran (10 ml) was heated to reflux for 15 hours. The mixturewas evaporated to remove the organic solvents and the residue wasextracted with diethyl ether. The organic layer was separated, washedwith a saturated aqueous solution of sodium chloride, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usinginitially methylene chloride and then increasingly polar mixtures ofmethylene chloride and acetone, up to a 9:1 v/v mixture, as eluent.There was thus obtained3-benzyloxy-2-(3-benzyloxyphenyl)propane-1,2-diol (2 g, 87%), as an oil.

A mixture of the product so obtained, tert-butyldimethylsilyl chloride(0.99 g), imidazole (0.45 g) and dimethylformamide (10 ml) was stirredat ambient temperature for 15 hours. The mixture was evaporated and theresidue was purified by column chromatography using methylene chlorideas eluent. There was thus obtained3-benzyloxy-2-(3-benzyloxyphenyl)-1-tert-butyldimethylsilyloxypropan-2-olas a colourless oil (2.14 g, 81%).

This product was methylated using the procedure described in Example 1.There was thus obtained3-benzyloxy-2-(3-benzyloxyphenyl)-2-methoxyprop-1-yltert-butyldimethylsilyl ether (2.02 g, 70%), as an oil.

A mixture of a portion (2 g) of the product so obtained, tetrahydrofuran(20 ml) and tetrabutylammonium fluoride (9 ml of a 1M solution intetrahydrofuran) was stirred at ambient temperature for 15 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and water. The organic layer was separated, washed with water,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using initially methylene chloride and then increasinglypolar mixtures of methylene chloride and diethyl ether, up to a 9:1 v/vmixture, as eluent. There was thus obtained3-benzyloxy-2-(3-benzyloxyphenyl)-2-methoxypropan-1-ol (1.54 g, 99%).

A mixture of the product so obtained, 10% palladium-on-charcoal (0.18 g)and ethanol (12 ml) was stirred at ambient temperature under anatmosphere of hydrogen for 48 hours. The mixture was filtered andevaporated. There was thus obtained2-(3-hydroxyphenyl)-2-methoxypropane-1,3-diol (0.67 g, 82%), as an oil.

The product so obtained was reacted with 2-bromomethylnaphthalene usingthe procedure described in Example 5. There was thus obtained therequired starting material (0.68 g, 60%), m.p. 128°-129° C.

EXAMPLE 14

Sodium hydride (50% w/w dispersion in mineral oil, 0.024 g) was added toa mixture of(2RS,3SR)-3-(5-hydroxypyrid-3-yl)-3-methoxy-2-methyltetrahydrofuran(0.104 g) and dimethylformamide (5 ml) which had been cooled to -10° C.and the mixture was stirred at that temperature for 1 hour. The mixturewas cooled to -15° C., 3-phenylprop-2-ynyl bromide (0.097 g) was addedand the mixture was stirred for 1 hour. The mixture was partitionedbetween diethyl ether and a saturated aqueous ammonium chloridesolution. The organic phase was dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 3:2 v/v mixture ofmethylene chloride and diethyl ether as eluent. There was thus obtained(2RS,3SR)-3-methoxy-2-methyl-3-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]tetrahydrofuran(0.11 g, 68%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 2.25-2.8(m, 4H), 3.25(s,3H), 3.6-3.95(m, 1H), 3.95-4.3(m, 2H), 5.15(s, 2H), 7.25-7.5(m, 5H),8.0-8.15(m, 1H), 8.4-8.6(m, 2H).

The (2RS,3SR)-3-(5-hydroxyprid-5-yl)-3-methoxy-2-methyltetrahydrofuranused as a starting material was obtained as follows:

Sodium hydride (50% w/w dispersion in mineral oil, 5 g) was addedportionwise to a mixture of benzyl alcohol (12.4 g) anddimethylformamide (150 ml) which had been cooled to 0° C. The mixturewas allowed to warm to ambient temperature and was stirred for 1 hour.3,5-Dibromopyridine (25.2 g) was added and the mixture was heated to 60°C. for 2 hours. The mixture was cooled to ambient temperature andpartitioned between ethyl acetate and a dilute aqueous potassiumcarbonate solution. The organic layer was washed with a dilute aqueoushydrochloric acid solution and with a saturated aqueous sodium chloridesolution, dried (MgSO₄) and evaporated. The residue was a red oil whichon trituration under petroleum ether (b.p. 60°-80° C.) gave5-benzyloxy-3-bromopyridine (18.6 g, 67%), m.p. 65°-67° C.

A solution of a portion (11.5 g) of this product in diethyl ether (500ml) was cooled to -50° C. and n-butyl-lithium (1.5M in hexane, 32 ml)was added dropwise. The mixture was stirred at -50° C. for 20 minutes,further cooled to -60° C. and a solution of2-methyltetrahydrofuran-3-one (5 g) in diethyl ether (50 ml) was added.The mixture was stirred at -60° C. for 1 hour and at -30° C. for 30minutes. A saturated aqueous ammonium chloride solution (200 ml) wasadded and the mixture was extracted with ethyl acetate (3×50 ml). Thecombined organic extracts were washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 7:3 v/v mixture of toluene andethyl acetate as eluent. There was thus obtained(2RS,3SR)-3-(5-benzyloxypyrid-3-yl)-3 -hydroxy-2-methyltetrahydrofuran(7.8 g, 63%), as an oil; the 2-methyl and 3-hydroxy groups being in acis-relationship.

NMR Spectrum (CDCl₃, delta values) 1.1(d, 3H), 2.3-2.8(m, 2H),3.8-4.3(m, 3H), 5.1(s, 2H), 7.35(s, 5H), 7.6(m, 1H), 8.3(m, 2H).

The product so obtained was converted, using the procedures described inExample 3 and in the portion of Example 5 which is concerned with thepreparation of starting materials, to the required starting material(90%), as an oil.

NMR Spectrum (CDCl₃, delta value) 1.15(d, 3H), 2.45(t, 2H), 3.10(s, 3H),3.69-3.9(m, 1H), 3.9-4.3(m, 2H), 7.25-7.4(m, 1H), 8.0-8.3(m, 2H).

EXAMPLE 15

The procedure described in Example 5 was repeated using the appropriatealkyl bromide and the appropriate phenol. There were thus obtained thecompounds described in the following table:

                  TABLE IV                                                        ______________________________________                                         ##STR6##                                                                     Ex. 15                                                                        Compd.                            m.p.   Yield                                No.    Ar.sup.1   Ar.sup.2   R.sup.1                                                                            (°C.)                                                                         (%)                                  ______________________________________                                        .sup. 1.sup.a                                                                        6-fluoro-  5-fluoro-1,3-                                                                            Me   85     88                                          naphth-2-yl                                                                              phenylene                                                   2      7-fluoro-  5-fluoro-1,3-                                                                            Me   109-110                                                                              76                                          naphth-2-yl                                                                              phenylene                                                   .sup. 3.sup.b                                                                        6,7-difluoro-                                                                            5-fluoro-1,3-                                                                            Me   oil    54                                          naphth-2-yl                                                                              phenylene                                                   4      5-cyano-   5-fluoro-1,3-                                                                            Me   134-136                                                                              41                                          naphth-2-yl                                                                              phenylene                                                   5      7-difluoro-                                                                              5-fluoro-1,3-                                                                            Me   89     84                                          methyl-    phenylene                                                          naphth-2-yl                                                            6      7-methyl-  5-fluoro-1,3-                                                                            Me   114    91                                          naphth-2-yl                                                                              phenylene                                                   7      4-cyano-   5-fluoro-1,3-                                                                            Me   133-134                                                                              82                                          phenyl     phenylene                                                    8*    4-methyl-  5-fluoro-1,3-                                                                            Me   72-74  66                                          thiophenyl phenylene                                                   9      3-methoxy- 5-fluoro-1,3-                                                                            Me    97-100                                                                              85                                          carbonyl-  phenylene                                                          phenyl                                                                 10.sup.c                                                                             4-tert-butyl-                                                                            5-fluoro-1,3-                                                                            Me   oil    70                                          phenyl     phenylene                                                   11.sup.d                                                                             4-n-propyl-                                                                              5-fluoro-1,3-                                                                            Me   oil    84                                          phenyl     phenylene                                                   12.sup.e                                                                             7-fluoro-  5-trifluoro-                                                                             Et   88-89  86                                          naphth-2-yl                                                                              methyl-                                                                       1,3-phenylene                                               ______________________________________                                    

a. The 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran used as astarting material was obtained as follows:

A solution of n-butyl-lithium (22 ml of a 1.6M solution in hexane) wasadded over 15 minutes to a solution of benzyl 3-bromo-5-fluorophenylether (9.75 g) in tetrahydrofuran (150 ml) which had been cooled to -75°C. and the mixture was stirred at this temperature for 1 hour. Asolution of tetrahydropyran-4-one (3.47 g) in tetrahydrofuran (10 ml)was added over a further 15 minutes and the mixture was stirred at -75°C. for 1 hour. The mixture was allowed to warm to 0° C. overapproximately 2 hours. A saturated aqueous ammonium chloride solution(50 ml) was added and the organic phase was separated. The aqueous phasewas extracted with ethyl acetate (3×30 ml). The combined organic phaseswere dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 2:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained 4-(3-benzyloxy-5-fluorophenyl)-4-hydroxytetrahydropyran (7.4 g, 70%), as anoil.

NMR Spectrum (CDCl₃, delta values) 1.6(m, 2H), 2.05-2.2(m, 2H),3.8-4.0(m, 4H), 5.05(s, 2H), 6.6(d, 1H), 6.8(d 1H), 6.9(s, 1H),7.15-7.45(m, 5H).

After appropriate repetition of the above reaction, a mixture of theproduct so obtained (12.1 g), sodium hydride (50% w/w dispersion inmineral oil; 2.11 g) and tetrahydrofuran (150 ml) was stirred at ambienttemperature for 1 hour. The mixture was cooled to 0° C. and methyliodide (3.75 ml) was added. The mixture was stirred at ambienttemperature for 15 hours. Aqueous 2N hydrochloric acid solution wasadded until no further effervescence occurred and the organic solventwas evaporated. The residue was partitioned between ethyl acetate andwater. The organic phase was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. There was thus obtained4-(3-benzyloxy-5-fluorophenyl)-4-methoxytetrahydropyran, as a lightyellow oil (12.5 g), which was used without further purification.

A mixture of the product so obtained, 10% palladium-on-charcoal catalyst(0.7 g) and absolute ethanol (100 ml) was stirred under an atmosphere ofhydrogen for 3 hours. The mixture was filtered and evaporated. There wasthus obtained the required starting material (7.7 g, 86%), m.p.123°-124° C.

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.92(m, 4H), 2.97(s, 3H), 3.80(m, 4H), 5.19(s,2H), 6.66-6.85(m, 3H), 7.5-7.61(m, 3H), 7.81(d, 2H).

c. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.35(s, 9H), 1.85-2.05(m, 4H), 3.0(s, 3H),3.75-3.90(m, 4H), 5.0(s, 2H), 6.6(d of t's, 1H), 6.7(d of t's, 1H),6.8(t, 1H), 7.35(d, 2H), 7.4(d, 2H).

d. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 0.98(t, 3H), 1.62(m, 2H), 1.9-1.98(m, 4H), 2.6(t,2H), 2.97(s, 3H), 3.78-3.85(m, 4H), 5.01(s, 2H), 6.61(d of t's, 1H),6.7(d of t's, 1H), 6.78(t, 1H), 7.19(d, 2H), 7.23(d, 2H).

e. The 4-ethoxy-4-(3-hydroxy-5-trifluoromethylphenyl)tetrahydropyranused as a starting material was obtained as follows:

Sodium hydride (55% w/w dispersion in mineral oil; 4.36 g) was addedportionwise to a mixture of benzyl alcohol (9.82 ml) anddimethylacetamide (136 ml) which had been cooled in an ice-bath. Themixture was stirred at ambient temperature for 1.5 hours and thenrecooled in an ice-bath. A solution of3-fluoro-5-trifluoromethylbromobenzene (22.1 g) in dimethylacetamide(136 ml) was added and the mixture was stirred at ambient temperaturefor 2 hours. The mixture was evaporated and the residue was partitionedbetween diethyl ether and water. The organic phase was washed with asaturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usinghexane as eluent. There was thus obtained3-benzyloxy-5-trifluoromethylbromobenzene (23.1 g, 77%), as a colourlessliquid.

NMR Spectrum 5.07(s, 2H), 7.15-7.35(3 s's, 3H), 7.36-7.42(m, 5H).

A solution of n-butyl-lithium (25.9 ml of a 1.6M solution in hexane) wasadded dropwise to a solution of a portion (13.75 g) of the compound soobtained in tetrahydrofuran (150 ml) which had been cooled to -70° C.The mixture was stirred at this temperature for 1 hour. A solution oftetrahydropyran-4-one (4.15 g) in tetrahydrofuran (5 ml) was addeddropwise and the mixture was stirred at -70° C. for 1 hour, and thenallowed to warm to 0° C. A saturated aqueous ammonium chloride solution(100 ml) was added and the mixture was extracted with diethyl ether. Theorganic phase was washed with a saturated aqueous sodium chloridesolution, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 4:1 v/v mixture of toluene and ethylacetate as eluent. There was thus obtained4-(3-benzyloxy-5-trifluoromethylphenyl)-4-hydroxytetrahydropyran (11.5g, 79%), as a solid.

NMR Spectrum (CDCl₃, delta values) 1.6-1.72(m, 2H), 2.05-2.25(m, 2H),3.6-4.0(m, 4H), 5.12(s, 2H), 7.1-7.5(m, 8H).

Powdered potassium hydroxide (1.5 g) was added to a solution of aportion (2.17 g) of the product so obtained in dimethylsulphoxide (15ml) and the mixture was stirred at ambient temperature for 10 minutes.Ethyl iodide (1.24 ml) was added and the mixture was stirred at ambienttemperature for 4 hours. The mixture was poured onto a mixture ofdiethyl ether and ice. The organic phase was separated, washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 10:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained4-(3-benzyloxy-5-trifluoromethylphenyl)-4-ethoxytetrahydropyran (1.75 g,74%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1-1.2(t, 3H), 1.8-2.1(m, 4H),3.0-3.1(q, 2H), 3.75-3.95(m, 4H), 5.1(s, 2H), 7.1-7.5(m, 8H).

A mixture of the product so obtained, 10% palladium-on-charcoal catalyst(0.35 g) and isopropanol (25 ml) was stirred under an atmosphere ofhydrogen for 3.5 hours. The mixture was filtered and evaporated. Therewas thus obtained the required starting material (1.3 g, 97%), as anoil.

NMR Spectrum (CDCl₃, delta values) 1.1-1.2(t, 3H), 1.9-2.1(m, 4H),3.05-3.15(q, 2H), 3.8-4.0(m, 4H), 7.0(m, 1H), 7.1(m, 1H),7.2(s, 1H).

Information concerning the preparation of appropriate starting materialsfor the compounds described within Example 15 is provided below:

(i) The procedure used to prepare the appropriate2bromomethylnaphthalenes for use in the preparation of compounds Nos. 1to 6 is illustrated below by the description of the preparation of2-bromomethyl-5-cyanonaphthalene. The other 2-bromomethylnaphthaleneswere prepared in analogous fashion. Thus:

A mixture of 5-cyano-2-methylnaphthalene (0.75 g), N-bromosuccinimide(0.81 g), 2,2'-azobisisobutyronitrile (0.05 g) and carbon tetrachloride(25 ml) was heated to reflux and irradiated with the light from a 275watt bulb for 1 hour. The mixture was cooled to ambient temperature andfiltered. The filtrate was evaporated and the residue was recrystallisedfrom carbon tetrachloride. There was thus obtained2-bromomethyl-5-cyanonaphthalene (0.64 g), m.p. 104°-106° C.

The procedure described immediately above was repeated except that theappropriate 2-methylnaphthalene was used in place of5-cyano-2-methylnaphthalene and the reaction product was purified bycolumn chromatography using increasingly polar mixtures of petroleumether (b.p. 60°-80° C.) and toluene as eluent. There were thus obtainedthe 2-bromomethylnaphthalenes listed below:

2-bromomethyl-6-fluoronaphthalene^(a), m.p. 48° C.;

2-bromomethyl-7-fluoronaphthalene^(b), m.p. 62° C.;

2-bromomethyl-6,7-difluoronaphthalene^(c), oil;

2-bromomethyl-7-difluoromethylnaphthalene^(d), m.p. 70°-71° C.; and

2-bromomethyl-7-methylnaphthalene, m.p. 100° C.

NOTES

a. 2-Methyl-6-fluoronaphthalene used as a starting material was obtainedas follows: 4-Fluorobenzyl chloride was reacted with acetylacetaldehydedimethylacetal using the procedure described for the correspondingreaction of 3-methylbenzyl chloride (Synthesis, 1974, 566). There wasthus obtained 4-(4-fluorophenyl)-3-hydroxy-3-methylbutanaldimethylacetal (b.p. 122°-130° C. at 0.2 mm Hg). A mixture of thematerial so obtained (15 g), glacial acetic acid (60 ml) and hydrobromicacid (48% w/v, 48 ml) was heated on a steam bath for 1 hour. The mixturewas evaporated and the residue was purified by column chromatographyusing petroleum ether (b.p. 60°-80° C.) as eluent. There was thusobtained 6-fluoro-2-methylnaphthalene (1 g).

b. The procedure described in Note a. above was repeated except that3-fluorobenzyl chloride was used. There was thus obtained7-fluoro-2-methylnaphthalene as a white solid.

c. The procedure described in Note a. above was repeated except that3,4-difluorobenzyl bromide was used as a starting material. There wasthus obtained 6,7-difluoro-2-methylnaphthalene as a white solid (11%),m.p. 63°-64° C.

d. 7-Difluoromethyl-2-methylnaphthalene used as a starting material wasobtained as follows:

A mixture of 2-methyl-7-naphthaldehyde (0.37 g; Bull Soc. Chim. Belg.,1985, 94, 205), diethylaminosulphur trifluoride (0.3 ml) and methylenechloride (3 ml) was stirred at ambient temperature for 16 hours. Asecond portion of the trifluoride (0.6 ml) was added and the reactionwas continued for a further 24 hours. The mixture was partitionedbetween methylene chloride and water. The organic layer was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 19:1 v/v mixture of petroleum ether (b.p. 60°-80°C.) and toluene as eluent. There was thus obtained7-difluoromethyl-2-methylnaphthalene as a solid (0.13 g).

(ii) 4-Methylthiobenzyl chloride used in the preparation of Compound No.8 was obtained as follows:

Thionyl chloride (1.56 ml) was added dropwise to a solution of4-methylthiobenzyl alcohol (3 g) in toluene (15 ml) which had beencooled to 0° C. The mixture was stirred for 1 hour and allowed to warmto ambient temperature. The mixture was evaporated and the residue waspurified by being washed through a small amount of silica using a 10:1v/v mixture of toluene and ethyl acetate as eluent. There was thusobtained the required starting material (2.8 g, 85%), as a liquid.

(iii) 4-n-Propylbenzyl bromide used in the preparation of Compound No.11 was obtained from 4-n-propylbenzoic acid by the conventionalprocedure of reduction with lithium aluminium hydride to form4-n-propylbenzyl alcohol and reaction of that product with phosphorustribromide.

EXAMPLE 16

Using the procedure described in Example 3,4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydropyran wasreacted with methyl iodide to give4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyran in98% yield, m.p. 109°-111° C.

The 4-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl)-4-hydroxytetrahydropyranused as a starting material was obtained as follows:

The procedures described in Note a. of Example 15 were repeated exceptthat the methylation step was omitted. There was thus obtained4-(5-fluoro-3-hydroxyphenyl)-4-hydroxytetrahydropyran (60%), m.p.158°-160° C.

A portion of (2.12 g) of the product so obtained was reacted with2-bromomethylnaphthalene (2.21 g) in the presence of potassium carbonate(2.8 g) and dimethylformamide (20 ml) using the procedure described inExample 5. There was thus obtained the required starting material (3.02g, 85%), m.p. 99°-101° C.

EXAMPLE 17

Powdered potassium hydroxide (0.2 g) and1,4,7,10,13,16-hexaoxacyclooctadecane (hereinafter 18-crown-6; 0.04 g)were added in succession to a mixture of4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydropyran(0.352 g) and tetrahydrofuran (2.5 ml) and the mixture was stirred atambient temperature for 5 minutes. Propargyl bromide (80% w/v solutionin toluene; 0.3 ml) was added and the mixture was stirred at ambienttemperature for 18 hours. The mixture was partitioned between ethylacetate and a saturated aqueous ammonium chloride solution. The organicphase was washed with a saturated aqueous sodium chloride solution,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of hexane and ethylacetate as eluent. There was thus obtained4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-(prop-2-ynyloxy)tetrahydropyran(0.32 g, 82%), m.p. 85°-87° C.

EXAMPLE 18

The procedure described in Example 17 was repeated using the appropriatealkyl halide and the appropriate 4-hydroxytetrahydropyran. There werethus obtained the compounds described in the following table:

                  TABLE V                                                         ______________________________________                                         ##STR7##                                                                     Ex. 18                             m.p.  Yield                                Compd. No.                                                                             Ar.sup.1  Ar.sup.2   R.sup.1                                                                            (°C.)                                                                        (%)                                  ______________________________________                                        1.sup.a  2-naphthyl                                                                              5-fluoro-1,3-                                                                            Et   64-65 66                                                      phenylene                                                  2.sup.b  2-naphthyl                                                                              5-fluoro-1,3-                                                                            allyl                                                                              oil   71                                                      phenylene                                                  ______________________________________                                    

N0TES

a. Ethyl iodide was used.

b. Allyl bromide was used. The product displayed the followingcharacteristic NMR signals (CDCl₃, delta values) 1.89-2.05(m, 4H), 3.6(dof t's, 2H), 3.75-3.95(m, 4H), 5.06-5.3(m, 2H), 5.2(s, 2H), 5.7-5.9(m,1H), 6.6-6.8(m, 2H), 6.88(t, 1H), 7.45-7.55(m, 3H), 7.8-7.9(m, 4H).

EXAMPLE 19

The procedure described in Example 5 was repeated using4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran in place of thecorresponding 2-methyltetrahydropyran. There was thus obtained4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(70%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.94(m, 4H), 2.99(s, 3H), 3.82(m,4H), 4.91(s, 2H), 6.65-6.88(m, 3H), 7.18-7.45(m, 5H);

Mass Spectrum P m/e 340;

Elemental Analysis Found C, 73.9; H, 5.6; C₂₁ H₂₁ FO₃ requires C, 74.1;H, 6.2%.

EXAMPLE 20

A solution of4-[5-fluoro-3-(2-propynyloxy)phenyl]-4-methoxytetrahydropyran (0.35 g)in acetonitrile (1.5 ml) was added to a mixture of 2-chlorophenyl iodide(0.36 g), bis(triphenylphosphine)palladium chloride (0.015 g),triethylamine (0.2 ml), cuprous iodide (0.015 g), and acetonitrile (4ml) and the mixture was stirred at 55° C. for 2 hours. The mixture wascooled to ambient temperature and partitioned between diethyl ether andwater. The organic phase was washed with water and with a saturatedaqueous sodium chloride solution, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 2:1 v/v mixture ofhexane and ethyl acetate as eluent. There was thus obtained4-[5-fluoro-3-(3-(2-chlorophenyl)prop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.26 g, 53%), m.p. 120°-122° C.

The 4-[5-fluoro-3-(2-propynyloxy)phenyl]-4-methoxytetrahydropyran usedas a starting material was obtained as follows:

A mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran (5.34g), propargyl bromide (80% w/v in toluene, 4.46 ml), potassium carbonate(5.52 g) and acetone (150 ml) was heated to reflux for 16 hours. Themixture was filtered and evaporated. The residue was partitioned betweenethyl acetate and water. The organic phase was washed with water andwith a saturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a2:1 v/v mixture of ethyl acetate and hexane as eluent. There was thusobtained the required starting material (5.77 g, 91%), m.p. 71°-72° C.

EXAMPLE 21

The procedure described in Example 20 was repeated using the appropriatephenyl iodide and the appropriate alkyne. There was thus obtained thecompounds described in the following table:

                  TABLE VI                                                        ______________________________________                                         ##STR8##                                                                     Ex. 21                                                                        Compd.                          m.p.  Yield                                   No.    Ar.sup.1         R.sup.1 (°C.)                                                                        (%)                                     ______________________________________                                         1.sup.a                                                                             3-chlorophenyl   Me      oil   64                                       2     4-chlorophenyl   Me      oil   55                                       3     4-fluorophenyl   Me      oil   52                                       4.sup.b                                                                             2-cyanophenyl    Me      oil   43                                       5.sup.c                                                                             3-cyanophenyl    Me      oil   72                                       6     4-cyanophenyl    Me      oil   43                                       7     2-trifluoromethylphenyl                                                                        Me      60-61 21                                       8     3-trifluoromethylphenyl                                                                        Me      oil   65                                       9     2-aminophenyl    Me      oil   38                                      10     3-aminophenyl    Me      oil   16                                      11     4-aminophenyl    Me      oil   23                                      .sup. 12.sup.d                                                                       2-methylsulphonylphenyl                                                                        Me      oil   35                                      .sup. 13.sup.e                                                                       2-cyanomethoxyphenyl                                                                           Me      oil   46                                       14.sup.f                                                                            3-cyanomethoxyphenyl                                                                           Me      oil   65                                      .sup. 15.sup.g                                                                       3-aminomethylphenyl                                                                            Me      oil   36                                      .sup. 16.sup.h                                                                       3-(2-cyanoprop-2-yl)-                                                                          Me      78-81 71                                             phenyl                                                                 17     3,5-dichlorophenyl                                                                             Me      oil   73                                      18     2,4-difluorophenyl                                                                             Me      oil   46                                      19     3,4-difluorophenyl                                                                             Me      oil   29                                      20     3,5-di(trifluoromethyl)-                                                                       Me      oil   77                                             phenyl                                                                  21.sup.i                                                                            2,5-dimethylphenyl                                                                             Me      oil   41                                      22     2-chloro-5-trifluoro-                                                                          Me      oil   77                                             methylphenyl                                                           23     2-cyano-3-fluorophenyl                                                                         Me      oil   57                                       24.sup.j                                                                            2-methylthio-5-  Me      oil   48                                             trifluoromethylphenyl                                                  ______________________________________                                    

NOTES

Unless otherwise stated the required substituted phenyl iodides werecommercially available.

For those products which were obtained as oils, characterisation was byway of NMR spectral data and by mass spectral analysis. Full NMRSpectral data are given below for Compound No. 1 of Table VI. Much ofthe corresponding data for the other compounds were very similar asexpected, therefore only characteristic signals are given. Unlessotherwise stated, each compound was dissolved in CDCl₃ and chemicalshift values are given on the delta scale.

a. NMR Spectrum 1.9(m, 4H), 2.95(s, 3H), 3.8(m, 4H), 4.9(s, 2H),6.6-6.9(m, 3H), 7.1-7.7(m, 4H).

b. 2-Cyanophenyl iodide, used as a starting material, was obtained from2-aminobenzonitrile using the process described in Note c. immediatelybelow. The product was obtained in 68% yield, m.p. 52°-54° C.

c. 3-Cyanophenyl iodide, used as a starting material, was obtained asfollows:

A solution of sodium nitrite (1.88 g) in water (5 ml) was added to amixture of 3-aminobenzonitrile (2.36 g) and aqueous hydrochloric acidsolution (50% w/v; 24 ml) which had been cooled in an ice-bath to atemperature in the range of 0°-5° C. The mixture was stirred at thistemperature for 5 minutes. A solution of potassium iodide (4.33 g) inwater (5 ml) was added and the mixture was stirred at 0°-5° C. for 30minutes and then at ambient temperature for 2 hours. The mixture wasextracted with ethyl acetate (3×25 ml). The combined extracts werewashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography to give the required starting material(2.7 g, 59%), as an oily solid.

NMR Spectrum (CDCl₃, delta values) 7.2(m, 1H), 7.6(m, 1H), 7.98(m, 2H).

d. NMR Spectrum 3.5(s, 3H, SO₂ Me). 2-Methylsulphonylphenyl iodide, usedas a starting material, was obtained as follows:

A solution of potassium peroxymonosulphate (5 g) in water (50 ml) wasadded to a mixture of 2-methylthiophenyl iodide (1.25 g) and methanol(60 ml) and the mixture was stirred at ambient temperature for 18 hours.The mixture was partitioned between methylene chloride and water. Theorganic phase was dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography using a 10:3 v/v mixture of hexane and ethylacetate as eluent. There was thus obtained the required startingmaterial (0.52 g, 37%), m.p. 110°-112° C.

e. NMR Spectrum 4.8(s, 2H, OCH₂ CN).

f. NMR Spectrum 4.75(s, 2H, OCH₂ CN).

g. NMR Spectrum 3.8(s, 2H, CH₂ NH₂).

h. 3-(2-Cyanoprop-2-yl)phenyl iodide, used as a starting material, wasobtained as follows:

A mixture of potassium cyanide (4 g) and tetra-n-butylammonium bromide(0.32 g) in water (20 ml) was added to a solution of 3-iodobenzylbromide (5.92 g) in methylene chloride (20 ml) and the mixture washeated to reflux for 2 hours. The organic phase was separated, washedwith water, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using methylene chloride as eluent to give3-iodophenylacetonitrile (4.4 g).

A mixture of the product so obtained, methyl iodide (5.6 ml) anddimethylformamide (20 ml) was added dropwise to a stirred suspension ofsodium hydride (60% w/w dispersion in mineral oil, 1.45 g) indimethylformamide which had been cooled to 5° C. The mixture was stirredand allowed to warm to ambient temperature. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated to give the required startingmaterial (4.5 g) which was used without further purification.

NMR Spectrum (CDCl₃, delta values) 1.7(s, 6H), 7.1(t, 1H), 7.45(d, 1H),7.65(d, 1H), 7.8(t, 1H).

i. NMR Spectrum 2.5(s, 6H, 2×CH₃).

j. NMR Spectrum 2.5(s, 3H, MeS).

EXAMPLE 22

The procedure described in Example 5 was repeated using the appropriatealkyl bromide and the appropriate phenol. There were thus obtained thecompounds described in the following table:

                  TABLE VII                                                       ______________________________________                                         ##STR9##                                                                     Ex. 22                              m.p. Yield                                Compd. No.                                                                             Ar.sup.1                                                                              Ar.sup.2     R.sup.1                                                                             (°C.)                                                                       (%)                                  ______________________________________                                        1.sup.a  phenyl  5-trifluoromethyl-                                                                         Me    oil  91                                                    1,3-phenylene                                                2.sup.b  phenyl  5-trifluoromethyl-                                                                         Et    oil  91                                                    1,3-phenylene                                                ______________________________________                                    

NOTES

a. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.9-2.0(m, 4H), 2.9(s, 3H), 3.7(m, 4H), 5.2(s,2H), 7.1-7.5(m, 8H).

The 4-(3-hydroxy-5-trifluoromethylphenyl)-4-methoxytetrahydropyran, usedas a starting material, was obtained from4-(3-benzyloxy-5-trifluoromethylphenyl)-4-hydroxytetrahydropyran usingthe procedures described in the 3rd and 4th paragraphs of Note e. belowTable IV in Example 15 except that methyl iodide was used in place ofethyl iodide. There was thus obtained the required starting material(78%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.9-2.1(m, 4H), 3.0(s, 3H),3.8-4.0(m, 4H), 5.95(s, 1H), 7.0(m, 1H), 7.1(m, 1H), 7.2(s, 1H).

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.1-1.2(t, 3H), 1.9-2.1(m, 4H), 3.05-3.15(q, 2H),3.8-3.9(m, 4H), 5.0(s, 2H), 7.15-7.45(m, 8H).

EXAMPLE 23

The procedure described in Example 3 was repeated using the appropriatealkyl halide and the appropriate alcohol. There was thus obtained thecompounds described in the following table:

                  TABLE VIII                                                      ______________________________________                                         ##STR10##                                                                    Ex. 23                                                                        Compd.                             m.p.  Yield                                No.    Ar.sup.1  Ar.sup.2     R.sup.1                                                                            (°C.)                                                                        (%)                                  ______________________________________                                        1.sup.a                                                                              7-fluoro- 5-trifluoromethyl-                                                                         Me   66-67 94                                          naphth-2-yl                                                                             1,3-phenylene                                                2.sup.b                                                                              7-fluoro- 5-trifluoromethyl-                                                                         allyl                                                                              oil   68                                          naphth-2-yl                                                                             1,3-phenylene                                                3.sup.c                                                                              6,7-difluoro-                                                                           5-trifluoromethyl-                                                                         allyl                                                                              oil   88                                          naphth-2-yl                                                                             1,3-phenylene                                                ______________________________________                                    

NOTES

a. The4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyranused as a starting material was obtained as follows:

4-(3-Benzyloxy-5-trifluoromethylphenyl)-4-hydroxytetrahydropyran (6 g)was hydrogenolysed using the procedure described in the 4th paragraph ofNote e. below Table IV in Example 15 to give4-hydroxy-4-(3-hydroxy-5-trifluoromethylphenyl)tetrahydropyran inquantitative yield, as an oil.

A portion (1.39 g) of the product so obtained was reacted with2-bromomethyl-7-fluoronaphthalene (1.27 g) using the procedure describedin Example 5. There was thus obtained the required starting material(2.23 g, 43%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.7-1.75(m, 2H). 2.05-2.25(m, 2H),3.85-4.0(m, 4H), 5.25(s, 2H), 7.1-7.95(m, 9H).

b. The product displayed the following characterisitc NMR signals(CDCl₃, delta values) 1.97-2.11(m, 4H), 3.54-3.58(m, 2H), 3.84-3.95(m,4H), 5.0-5.3(m, 2H), 5.25(s, 2H), 5.72-5.91(m, 1H), 7.18-7.89(m, 9H).

c. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.85-2.10(m, 4H), 3.5-3.65(m, 2H), 3.75-4.0(m,4H), 5.05-5.4(m, 4H), 5.7-5.9(m, 1H), 7.1-7.3(m, 3H), 7.45-7.65(m, 3H),7.7-7.9(m, 2H).

The4-[3-(6,7-difluoronaphth-2-ylmethoxy)-5trifluoromethylphenyl]-4-hydroxytetrahydropyranused as a starting material was obtained using the same proceduredescribed in Note a. above except that2-bromomethyl-6,7-difluoronaphthalene was used in place of2-bromomethyl-7-fluoronaphthalene.

EXAMPLE 24

4-Hydroxy-4-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]-tetrahydropyranwas alkylated with methyl iodide using the procedure described inExample 1 except that no 15-crown-5 was added. There was thus obtained4-methoxy-4-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]tetrahydropyran(72%), m.p. 112°-113° C.

The4-hydroxy-4-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]tetrahydropyran,used as a starting material was obtained as follows:

A solution of 3-phenylprop-2-yn-1-ol (19 g) in dimethylacetamide (100ml) was added to a stirred suspension of sodium hydride (50% w/wdispersion in mineral oil, 7.5 g) in dimethylacetamide (320 ml) and themixture was stirred at ambient temperature for 1 hour.1-Iodo-3,5-dinitrobenzene (42 g; J. Chem. Soc. (C), 1970, 1480) wasadded to the mixture portionwise and the resultant mixture was stirredat ambient temperature for 2 hours. The mixture was partitioned betweendiethyl ether and 2N aqueous hydrochloric acid solution. The organicphase was washed with water, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography using increasingly polar mixturesof petroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent.There was thus obtained 5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl iodide(31 g, 58%), as an oil.

NMR Spectrum (CD₃ SOCD₃, delta values) 5.25(s, 2H), 7.45(s, 5H), 7.9(m,2H), 8.15(m, 1H).

A solution of a portion (2.6 g) of the product so obtained intetrahydrofuran (100 ml) was cooled to -105° C. and n-butyl-lithium(1.2M in toluene; 4.3 ml) was added dropwise. The mixture was stirred at-100° C. for 10 minutes then tetrahydropyran-4-one (0.63 ml) was addeddropwise. The mixture was stirred at -100° C. for 20 minutes and thenallowed to warm to ambient temperature. The mixture was partitionedbetween diethyl ether and 2N aqueous hydrochloric acid solution. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 1:1 v/v mixture ofpetroleum ether (b.p. 40°-60° C.) and diethyl ether as eluent. There wasthus obtained the required starting material (2.2 g, 65%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.5-2.5(m, 5H), 3.75-4.0(m, 4H),5.0(s, 2H), 7.2-7.6(m, 6H), 7.8(m, 1H), 8.0(m, 1H).

EXAMPLE 25

A mixture of4-methoxy-4-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]tetrahydropyran(0.3 g), activated iron (1.5 g; obtained by stirring a mixture of ironpowder and 2N hydrochloric acid solution for 10 minutes, filtering themixture and washing and drying the solid), ferrous sulphate heptahydrate(0.15 g), water (4.5 ml) and methanol (21 ml) was stirred vigorously andheated to 80° C. for 45 minutes. The mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography using diethyl ether as eluent. There was thus obtained4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.23 g, 84%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.94(m, 4H), 3.0(s, 3H), 3.8(m, 4H),4.9(s, 2H), 6.35(m, 2H), 6.5(m, 1H), 7.35(m, 5H).

EXAMPLE 26

Sodium cyanoborohydride (0.56 g) was added portionwise to a mixture of4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran (1g), formaldehyde (2.5 ml of a 37% w/v solution in water) andacetonitrile (30 ml). The mixture was stirred at ambient temperature for15 minutes. Acetic acid (1 ml) was added and the mixture was stirred for2 hours. The mixture was partitioned between diethyl ether and water.The organic phase was separated, washed with 1N aqueous potassiumhydroxide solution and with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using diethyl ether aseluent. There was thus obtained4-[5-dimethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.87 g, 80%), as an oil.

NMR Spectrum (CDCl₃, delta values) 2.0(m, 4H), 2.95(s, 6H), 3.0(s, 3H),3.75-4.0(m, 4H), 4.9(s, 2H), 6.3-6.5(m, 3H), 7.2-7.55(m, 5H).

EXAMPLE 27

Sodium cyanate (0.17 g) was added portionwise to a mixture of4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.5 g), 2N hydrochloric acid solution (1 ml), water (2.5 ml) andethanol (2.5 ml) and the mixture was stirred at ambient temperature for15 hours. The mixture was extracted with methylene chloride. The organicphase was dried (MgSO₄) and evaporated. The residue was triturated undera mixture of dichloromethane and diethyl ether. There was thus obtained4-methoxy-4-[3-(3-phenylprop-2-ynyloxy)-5-ureidophenyl]tetrahydropyran(0.38 g, 67%), m.p. 164°-165° C.

EXAMPLE 28

Acetyl chloride (0.127 ml) was added to a mixture of4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.5 g), triethylamine (0.25 ml) and methylene chloride (10 ml) whichhad been cooled to 0° C. and the mixture was stirred at ambienttemperature for 2 hours. The mixture was partitioned between diethylether and water. The organic phase was dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using diethyl ether aseluent. There was thus obtained4-[5-acetamido-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.46 g, 83%), as an oil.

NMR Spectrum (CDCl₃, delta values) 2.0(m, 4H), 2.2(s, 3H), 3.0(s, 3H),3.7-3.95(m, 4H), 4.95(s, 2H), 6.85(m, 1H), 7.0(m, 1H), 7.15-7.55(m, 6H).

EXAMPLE 29

A mixture of4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran (1g), bromoacetonitrile (0.4 ml), potassium carbonate (0.49 g) anddimethylformamide (10 ml) was heated to 60° C. for 3 hours and to 80°for 2 hours. The mixture was cooled to ambient temperature andpartitioned between diethyl ether and water. The organic phase was dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained4-[5-cyanomethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.9 g, 81%), as an oil.

NMR Spectrum (CDCl₃, delta values) 2.0(m, 4H), 3.0(s, 3H), 3.85(m, 4H),4.1(s, 2H), 4.9(s, 2H), 6.35(m, 1H), 6.4(m, 1H), 6.65(m, 1H), 7.1-7.6(m,5H).

EXAMPLE 30

The procedure described in Example 29 was repeated except that ethylbromoacetate was used in place of bromoacetonitrile and that the mixturewas stirred at ambient temperature for 12 hours. There was thus obtained4-[5-ethoxycarbonylmethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(1.16 g, 92%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.29(t, 3H), 1.95(m, 4H), 2.99(s,3H), 3.7-4.0(m, 6H), 4.25(q, 2H), 4.9(s, 2H), 6.25(m, 1H), 6.35(m, 1H),6.55(m, 1H), 7.1-7.6(m, 5H).

EXAMPLE 31

A mixture of4-[5-ethoxycarbonylmethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.4 g), 2N aqueous sodium hydroxide solution (2 ml) and methanol (2 ml)was stirred at ambient temperature for 2 hours. The mixture was cooledto 0° C. and acidified by the addition of 2N aqueous hydrochloric acidsolution. The mixture was extracted with diethyl ether. The organicphase was dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 49:1 v/v mixture of methylene chloride andmethanol as eluent. There was thus obtained4-[5-carboxymethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.22 g, 59%), as an oil.

NMR Spectrum (CDCl₃, delta values) 2.0(m, 4H), 3.0(s, 3H), 3.6-4.1(m,6H), 4.9(s, 2H), 5.4(m, 2H), 6.15-6.45(m, 2H), 6.5(m, 1H), 7.1-7.6(m,5H).

EXAMPLE 32

Lithium aluminium hydride (0.03 g) was added portionwise to a solutionof4-[5-ethoxycarbonylmethylamino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.5 g) in diethyl ether (10 ml) which had been cooled to 0° C. and themixture was stirred at 0° C. for 30 minutes. Ice was added portionwiseto hydrolyse the excess of reducing agent. The organic phase wasseparated, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 4:1 v/v mixture of toluene and ethylacetate as eluent. There was thus obtained4-[5-(2-hydroxyethyl)amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(0.33 g, 73%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.94(m, 4H), 3.0(s, 3H), 3.3(t, 2H),3.6-4.0(m, 6H), 4.9(s, 2H), 6.2-6.45(m, 2H), 6.5(m, 1H), 7.1-7.55(m,5H).

EXAMPLE 33

A mixture of 4-(3,5-dihydroxyphenyl)-4-methoxytetrahydropyran (4.75 g),3-phenylprop-2-ynyl bromide (4.2 g), potassium carbonate (2.92 g) anddimethylformamide (50 ml) was stirred at ambient temperature for 12hours. The mixture was acidified by the addition of 2N hydrochloric acidsolution and extracted with diethyl ether. The organic extract was dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 4:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained4-[5-hydroxy-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(1.92 g, 27%), m.p. 141°-142° C.

The 4-(3,5-dihydroxyphenyl)-4-methoxytetrahydropyran, used as a startingmaterial, was obtained as follows:

3,5-Dihydroxyphenyl iodide (Tex. J. Sci., 1977, 28, 253) was reactedwith two equivalents of benzyl bromide using the procedure described inExample 3 to give 3,5-dibenzyloxyphenyl iodide (96%), as an oil. Thiswas reacted with n-butyl-lithium using the procedure described in theportion of Example 24 which is concerned with the preparation ofstarting materials and the organometallic reagent so formed was reactedwith tetrahydropyran-4-one using the procedure described in thatExample. There was thus obtained4-(3,5-dibenzyloxyphenyl)-4-hydroxytetrahydropyran (60%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.5-2.4(m, 4H), 3.75-4.0(m, 4H),5.05(s, 4H), 6.55(d of d's, 1H), 6.75(d, 2H), 7.4(m, 10H).

The product so obtained was methylated using the procedure described inExample 1. There was thus obtained4-(3,5-dibenzyloxyphenyl)-4-methoxytetrahydropyran (75%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.7-2.0(m, 4H), 2.35(s, 3H),3.5-3.8(m, 4H), 5.1(s, 4H), 6.7(s, 3H), 7.2-7.6(m, 10H).

The product so obtained was hydrogenolysed using the procedure describedin the portion of Example 5 which is concerned with the preparation ofstarting materials. There was thus obtained the required startingmaterial (90%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.7-2.0(m, 4H), 2.3(s, 3H),3.5-3.8(m, 4H), 6.1-6.4(m, 3H).

EXAMPLE 34

4-[5-Hydroxy-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyranwas reacted with methyl iodide using the procedure described in Example5. There was thus obtained4-methoxy-4-[5-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]tetrahydropyran(85%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.95(m, 4H), 3.0(s, 3H), 3.8(m, 7H),4.9(s, 2H), 6.5-6.75(m, 3H), 7.2-7.6(m, 5H).

EXAMPLE 35

The procedure described in Example 34 was repeated except thatbromoacetonitrile was used in place of methyl iodide and the reactionmixture was heated to 60° C. for 4 hours. There was thus obtained4-[5-cyanomethoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran(45%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.95(m, 4H), 3.0(s, 3H), 3.9(m, 4H),4.8(s, 2H), 5.0(s, 2H), 6.65-6.75(m, 2H), 6.9(m, 1H), 7.2-7.6(m, 5H).

EXAMPLE 36

4-Hydroxy-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]tetrahydropyran wasalkylated with methyl iodide using the procedure described in Example 1.There was thus obtained4-methoxy-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]tetrahydropyran (62%),as an oil.

NMR Spectrum (CDCl₃, delta values) 1.8-2.25(m, 4H), 3.0(s, 3H),3.75-4.1(m, 4H), 4.98(s, 2H), 7.25-7.6(m, 6H), 8.25-8.5(m, 2H).

The 4-hydroxy-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]tetrahydropyran,used as a starting material, was obtained as follows:

3-Phenylprop-2-ynyl bromide (0.195 g) was added dropwise to a mixture of3-bromo-5-hydroxypyridine (0.174 g; UK Patent Applic. No. 2025953),potassium carbonate (0.14 g) and dimethylformamide (5 ml) which had beencooled to -15° C. The mixture was stirred at -15° C. for 24 hours. Themixture was partitioned between ethyl acetate and a saturated aqueousammonium chloride solution. The organic phase was dried (MgSO₄) andevaporated. The residue was purified by column chromatography usingmethylene chloride as eluent. There was thus obtained3-bromo-5-(3-phenylprop-2-ynyloxy)pyridine (0.14 g, 49%), as an oil.

NMR Spectrum (CDCl₃, delta values) 4.95(s, 2H), 7.25-8.1(m, 6H),8.25-8.5(m, 2H).

After appropriate repetition of the above reaction the product soobtained was treated as follows:

n-Butyl-lithium (1.6M in hexane, 6.5 ml) was added dropwise to asolution of the product so obtained (2.88 g) in tetrahydrofuran (130 ml)which had been cooled to -110° C. The mixture was stirred at thistemperature for 10 minutes and then tetrahydropyran-4-one (1 g) wasadded dropwise. The mixture was allowed to warm to -10° C. over a periodof 1 hour. The mixture was partitioned between diethyl ether and asaturated aqueous ammonium chloride solution. The organic phase wasdried (MgSO₄) and evaporated and the residue was purified by columnchromatography using 50:50:1 v/v mixture of methylene chloride, diethylether and methanol as eluent. There was thus obtained the requiredstarting material (1.12 g, 36%), m.p. 198°-200° C.

EXAMPLE 37

Sodium hydride (50% w/w dispersion in mineral oil, 0.048 g) was added toa solution of4-hydroxy-4-[3-(naphth-2-ylmethoxy)pyridazin-5-yl]tetrahydropyran (0.34g) in dimethylformamide (12 ml) which had been cooled to -20° C. and themixture was stirred at this temperature for 1 hour. Methyl iodide (0.142g) was added and the mixture was stirred at -20° C. for 1 hour. Themixture was partitioned between diethyl ether and water. The organicphase was dried (MgSO₄) and evaporated and the residue was purified bycolumn chromatography using a 50:50:1 v/v mixture of methylene chloride,diethyl ether and methanol as eluent. There was thus obtained4-methoxy-4-[3-(naphth-2-ylmethoxy)pyridazin-5-yl]tetrahydropyran (0.27g, 77%), m.p. 90°-91° C.

The 4-hydroxy-4-[3-naphth-2-ylmethoxy)pyridazin-5-yl]tetrahydropyranused as a starting material was obtained as follows:

A mixture of 2-bromomethylnaphthalene (0.44 g),5-bromo-3-hydroxypyridazine (0.175 g; Spanish Patent Application No.454136), silver carbonate (0.167 g) and benzene (5 ml) was stirred atambient temperature for 72 hours. The mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography using methylene chloride as eluent. There was thusobtained 5-bromo-3-(naphth-2-ylmethoxy)pyridazine (0.165 g, 52%).

The product so obtained was reacted with tetrahydropyran-4-one using theprocedure described in the second paragraph of the portion of Example 36which is concerned with the preparation of starting materials. There wasthus obtained the required starting material (52%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.5-2.25(m, 4H), 3.5-4.0(m, 4H),5.6(s, 2H), 7.1(s, 1H), 7.25-8.0(m, 7H), 9.0(m, 1H).

EXAMPLE 38

Sodium periodate (0.426 g) was added to a stirred suspension of4-[5-fluoro-3-(4-methylthiobenzyloxy)phenyl-4-methoxytetrahydropyran(0.6 g), methanol (30 ml) and water (2 ml) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and wasstirred for 64 hours. The mixture was partitioned between ethyl acetateand water. The organic phase was washed with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using ethyl acetate as eluent. Therewas thus obtained4-[5-fluoro-3-(4-methylsulphinylbenzyloxy)phenyl]-4-methoxytetrahydropyran(0.44 g, 70%), m.p. 104°-105° C.

EXAMPLE 39

A solution of potassium peroxymonosulphate (2 g) in water (10 ml) wasadded to a mixture of4-[5-fluoro-3-(4-methylthiobenzyloxy)phenyl]-4-methoxytetrahydropyran(0.87 g), methanol (25 ml) and tetrahydrofuran (15 ml) and the cloudymixture was stirred at ambient temperature for 16 hours. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with a saturated aqueous sodium chloride solution, dried (MgSO₄)and evaporated. The residual solid was dissolved in ethyl acetate andprecipitated by the addition of petroleum ether (b.p. 60°-80° C.). Therewas thus obtained4-[5-fluoro-3-(4-methylsulphonylbenzyloxy)phenyl]-4-methoxytetrahydropyran(0.53 g, 62%), m.p. 123°-124° C.

EXAMPLE 40

A mixture of4-[3-(3-(3-aminophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran(0.21 g), acetic anhydride (1.5 ml) and pyridine (1.5 ml) was allowed tostand at ambient temperature for 16 hours. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 1:2 v/v mixture of hexane and ethyl acetate aseluent. There was thus obtained4-[3-(3-(3-acetamidophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran(0.14 g, 59%), m.p. 124°-126° C.

EXAMPLE 41

A mixture of 4-hydroxy-4-(4-(naphth-2-ylmethoxy)phenyl)tetrahydropyran(0.39 g), powdered potassium hydroxide (0.262 g), methyl iodide (0.332g) and dimethylsulphoxide (10 ml) was stirred at ambient temperature for15 hours. The mixture was evaporated and the residue was purified bycolumn chromatography using a 97:3 v/v mixture of methylene chloride andmethanol as eluent. There was thus obtained4-methoxy-4-(4-(naphth-2-ylmethoxy)phenyl)tetrahydropyran (0.18 g, 27%),m.p. 135°-136° C.

The 4-hydroxy-4-(4-naphth-2-ylmethoxy)phenyl)tetrahydropyran, used as astarting material, was obtained as follows:

Using the procedure described in Example 5, 2-bromomethylnaphthalene wasreacted with 4-bromophenol to give 4-(naphth-2-ylmethoxy)bromobenzene(99%), m.p. 104°-106° C.

Using the procedure described in the 2nd paragraph of the portion ofExample 3 which is concerned with the preparation of starting materials,the product obtained above was reacted with tetrahydropyran-4-one togive the required starting material (29%), m.p. 166°-168° C.

EXAMPLE 42

Using the procedure described in Example 3,4-hydroxy-4-(3-methoxy-4-(naphth-2-ylmethoxy)phenyl)tetrahydropyran (0.5g) was reacted with methyl iodide (2 ml) to give4-methoxy-4-(3-methoxy-4-(naphth-2-ylmethoxy)phenyl)tetrahydropyran(0.27 g, 52%), m.p. 129° C. (recrystallised from ethyl acetate).

The 4-hydroxy-4-(3-methoxy-4-(naphth-2-ylmethoxy)phenyltetrahydropyranused as a starting material was obtained as follows:

Using the procedure described in Example 5, 2-bromomethylnaphthalene wasreacted with 4-bromo-2-methoxyphenol to give3-methoxy-4-(naphth-2-ylmethoxy)bromobenzene (62%), m.p. 108° C.

Using the procedure described in the 2nd paragraph of the portion ofExample 3 which is concerned with the preparation of starting materials,the product obtained above was reacted with tetrahydropyran-4-one togive the required starting material (44%), m.p. 150°-151° C.(recrystallised from ethyl acetate).

EXAMPLE 43

Using the procedure described in Example 1, except that no 15-crown-5was used,4-(3-cyano-4-(naphth-2-ylmethoxy)phenyl)-4-hydroxytetrahydropyran (0.18g) was reacted with methyl iodide. There was thus obtained4-(3-cyano-4-(naphth-2-ylmethoxy)phenyl)-4-methoxytetrahydropyran (0.11g, 59%), m.p. 161°-164° C. [recrystallised from a mixture of petroleumether (b.p. 60°-80° C.) and methylene chloride].

The 4-(3-cyano-4-(naphth-2-ylmethoxy)phenyl-4-hydroxytetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in Example 5, 2-bromomethylnaphthalene wasreacted with methyl 5-iodosalicylate to give methyl5-iodo-2-(naphth-2-ylmethoxy)benzoate (68%). Using conventionalprocedures the ester was hydrolysed with base to give the correspondingacid; the acid chloride was prepared by reaction with oxalyl chloride;and the acid chloride was reacted with ethanolic ammonia to give5-iodo-2-(naphth-2-ylmethoxy)benzamide (84% from the ester), m.p. 163°C. The benzamide so obtained was reacted with trifluoroacetic anhydridein the presence of pyridine and dimethoxyethane as reaction solvent.There was thus obtained 3-cyano-4-(naphth-2-ylmethoxy)phenyl iodide(72%), m.p. 108°-110° C.

Using the procedure described in the 2nd paragraph of the portion ofExample 24 which is concerned with the preparation of startingmaterials, the iodide so obtained (0.77 g) was reacted withtetrahydropyran-4-one (0.2 ml) to give the required starting material(0.18 g, 25%), m.p. 144°-145° C.

EXAMPLE 44

The procedure described in Example 3 was repeated using the appropriatealkyl halide and the appropriate alcohol. There were thus obtained thecompounds described in the following table:

                                      TABLE IX                                    __________________________________________________________________________     ##STR11##                                                                    Ex. 44                                                                        Compd. No.                                                                           Ar.sup.1    Ar.sup.2        R.sup.1                                                                          R    m.p. (°C.)                                                                   Yield (%)                    __________________________________________________________________________     1.sup.a                                                                             2-naphthyl  1,3-phenylene   Me alpha-Me                                                                           48-50 30                            2.sup.b                                                                             2-naphthyl  1,3-phenylene   Me beta-Me                                                                            oil   72                            3.sup.c                                                                             2-naphthyl  1,3-phenylene   allyl                                                                            alpha-Me                                                                           oil   13                            4.sup.d                                                                             2-naphthyl  5-fluoro-1,3-phenylene                                                                        Me alpha-Me                                                                           oil   42                            5.sup.e                                                                             2-naphthyl  5-fluoro-1,3-phenylene                                                                        Me beta-Me                                                                            oil   57                            6.sup.f                                                                             2-naphthyl  5-fluoro-1,3-phenylene                                                                        allyl                                                                            alpha-Me                                                                           oil   55                            7.sup.g                                                                             2-naphthyl  5-fluoro-1,3-phenylene                                                                        allyl                                                                            beta-Me                                                                            oil   48                            8.sup.h                                                                             2-naphthyl  5-trifluoro-methyl-1,3-phenylene                                                              Me alpha-Me                                                                           oil   66                            9.sup.i                                                                             2-naphthyl  5-trifluoro-methyl-1,3-phenylene                                                              Me beta-Me                                                                            oil   47                           10.sup.j                                                                             2-naphthyl  5-trifluoro-methyl-1,3-phenylene                                                              Et beta-Me                                                                            oil   68                           11.sup.k                                                                             7-fluoronaphth-2-yl                                                                       1,3-phenylene   allyl                                                                            alpha-Me                                                                           oil   55                           12.sup.l                                                                             6,7-difluoro-naphth-2-yl                                                                  1,3-phenylene   allyl                                                                            alpha-Me                                                                           oil   59                           13.sup.m                                                                             2-naphthyl  5-fluoro-1,3-phenylene                                                                        Et alpha-Me                                                                           oil   33                           __________________________________________________________________________

NOTES

a. Methyl iodide was used as the alkylating agent.

The(2RS,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,used as a starting material, was obtained as follows:

A solution of n-butyl-lithium (1.6M in hexane, 6.25 ml) was added to asolution of 3-(naphth-2-ylmethoxy)bromobenzene (3.13 g) intetrahydrofuran (60 ml) which had been cooled to -70° C. and the mixturewas stirred at this temperature for 5 minutes. Magnesium bromide (25 mlof a 0.5M solution in a 1:1 v/v mixture of toluene and diethyl ether;prepared as described in J. Org. Chem., 1979, 44, 3280) was added andthe mixture was stirred at -70° C. for 5 minutes. A solution of2-methyltetrahydropyran-4-one (1.14 g) in tetrahydrofuran (5 ml) wasadded and the mixture was stirred at -70° C. for 10 minutes and thenallowed to warm to ambient temperature. The mixture was concentrated toapproxmately one third of the original volume and poured into water (300ml). The mixture was neutralised by the addition of 2N hydrochloric acidsolution and extracted with diethyl ether (2×150 ml). The combinedextracts were washed with water and with a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue, containinga mixture of diastereoisomers, was purified and the isomers wereseparated by column chromatography using a 2:1 v/v mixture of hexane andethyl acetate as eluent.

There were thus obtained: a less polar isomer,(2RS,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran(1 g, 29%), as an oil, i.e. the 2-methyl and 4-hydroxy substituents arein a trans relationship,

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.5-2.2(m, 4H),3.9-4.0(m, 3H), 5.25(s, 2H), 6.9-7.9(m, 11H); and a more polar isomer,(2SR,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran(0.8 g, 23%), as an oil, i.e. the 2-methyl and 4-hydroxy substituentsare in a cis-relationship,

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.5-2.4(m, 4H), 3.4(m,2H), 3.9(m, 1H), 5.25(s, 2H), 6.9-7.9(m, 11H).

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 1.6-2.4(m, 4H), 2.85(s, 3H), 3.4(m,2H), 3.9(m, 1H), 5.25(s, 2H), 6.9-7.9(m, 11H).

The (2SR,4SR)-isomer, described in Note a. above, was used as therequired starting material.

c. Allyl bromide was used as the alkylating agent, potassium hydroxideas the base and dimethylsulphoxide as the solvent, and the proceduredescribed in the 3rd paragraph of the portion of Note e. below Table IVin Example 15 was utilised. The product displayed the followingcharacteristic NMR signals (CDCl₃, delta values) 1.2(d, 3H), 1.5-2.0(m,4H), 3.6(m, 2H), 3.9(m, 3H), 5.2(m, 4H), 5.8(m, 1H), 6.8-7.9(m, 11H).

d. Methyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 1.2(m,3H), 1.5-1.9(m, 4H), 2.94(s, 3H), 3.8(m, 3H), 5.2(s, 2H), 6.6-7.8(m,10H).

The(2RS,4SR)-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxy-2-methyltetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in the first paragraph of the portion ofExample 3 which is concerned with the preparation of starting materials,2-naphthalenemethanol was reacted with 1-bromo-3,5-difluorobenzene togive 5-fluoro-3-(naphth-2-ylmethoxy)bromobenzene (92%), m.p. 65°-67° C.

Using the procedure described in Note a. above, the product so obtainedwas reacted with 2-methyltetrahydropyran-4-one to give a less polarisomer,(2RS,4SR)-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxy-2-methyltetrahydropyran(44%), as an oil,

NMR Spectrum (CDCl₃, delta values) 1.2 (d, 3H), 1.4-1.6(m, 4H), 3.85(m,3H), 5.2(s, 2H), 6.6-7.8(m, 10H); and a more polar isomer, thecorresponding (2SR,4SR)-isomer (29%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1(d, 3H), 1.6(m, 2H), 2.2(m, 2H),3.3(m, 2H), 3.85(m, 1H), 5.2(s, 2H), 6.6-7.8(m, 10H).

e. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.13(d, 3H), 1.6(m, 2H), 2.28(m, 2H), 2.88(s, 3H),3.36(m, 2H), 3.94(m, 1H), 5.2(s, 2H), 6.7-7.8(m, 10H).

The (2SR,4SR-isomer, described in Note d. above, was used as therequired starting material.

f. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 1.2(m,3H), 1.5-1.9(m, 4H), 3.6(m, 2H), 3.9(m, 3H), 5.2(m, 4H), 5.8(m, 1H),6.6-7.8(m, 10H).

g. Allyl bromide was used as the alkylating agent and the(2SR,4SR)-isomer, described in Note d. above, was used as the alcohol.The product displayed the following NMR signals (CDCl₃, delta values)1.2(m, 3H), 1.7-1.9(m, 2H), 2.3(m, 2H), 3.4(m, 2H), 3.55(m, 2H), 3.94(m,1H), 5.1(m, 2H), 5.2(s, 2H), 5.7(m, 1H), 6.7-7.9(m, 10H).

h. Methyl iodide was used as the alkylating agent. The product displayedthe following NMR signals (CDCl₃, delta values) 1.2(m, 3H), 1.5-1.9(m,4H), 2.95(s, 3H), 3.8(m, 3H), 5.2(s, 2H), 7.2-7.8(m, 10H).

The(2RS,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyranused as a starting material was obtained as follows:

Using the procedure described in the first paragraph of Note e. belowTable IV in Example 15, 2-naphthalenemethanol was reacted with3-fluoro-5-trifluoromethylbromobenzene to give3-(naphth-2-ylmethoxy)-5-trifluoromethylbromobenzene (80%), m.p. 68°-70°C.

Using the procedure described in Note a. above, the product so obtainedwas reacted with 2-methyltetrahydropyran-4-one to give a less polarisomer,(2RS,4SR)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyran(18%), as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer (12%), as an oil.

i. The product displayed the following characterisitic NMR signals(CDCl₃, delta values) 1.1(d, 3H), 1.6(m, 2H), 2.3(m, 2H), 2.9(s, 3H),3.4(m, 2H), 3.9(m, 1H), 5.2(s, 2H), 7.2-7.8(m, 10H).

j. Ethyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.1(d, 3H), 1.6-1.9(m, 2H), 2.3(m, 2H), 3.0(q, 2H), 3.4(m, 2H),3.9(m, 1H), 5.2(s, 2H), 7.2-7.8(m, 10H).

k. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 1.2(d,3H), 1.6(m, 1H), 2.0(m, 3H), 3.6(m, 2H), 3.95-4.1(m, 3H), 5.1(m, 1H),5.2-5.3(m, 3H), 5.8(m, 1H), 6.9-7.9(m, 10H).

The(2RS,4SR)-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-hydroxy-2-methyltetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in Exampe 5, 3-bromophenol was reactedwith benzyl bromide to give 3-benzyloxybromobenzene (97%), as a whitesolid.

Using the procedure described in the portion of Example 1 which isconcerned with the preparation of starting materials, a Grignard reagentwas prepared from 3-benzyloxybromobenzene (10.5 g) and2-methyltetrahydropyran-4-one (2.28 g) was added. The mixture wasstirred at ambient temperature for 3 hours, acidified by the addition of2N hydrochloric acid solution and extracted with ethyl acetate. Columnchromatography, using a 10:3 v/v mixture of toluene and ethyl acetate aseluent, gave a less polar isomer,(2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (2.45g, 41%), as an oil,

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6-1.8(m, 4H),2.0-2.2(m,1H), 3.9-4.1(m, 3H), 5.1(s, 2H), 6.85-7.45(m, 9H); and a more polarisomer,(2SR,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.38g, 23%), as an oil,

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6-2.05(m, 4H),2.3-2.45(m, 1H), 3.3-3.5(m, 2H), 3.9-4.0(m, 1H), 5.1(s, 2H), 6.9-7.5(m,9H).

After repetition of the above steps, a mixture of the (2RS,4SR)-isomer(5.1 g), 10% palladium-on-charcoal catalyst (0.5 g) and ethanol (100 ml)was stirred under an atmosphere of hydrogen for 15 hours. The mixturewas filtered and the filtrate was evaporated. There was thus obtained(2RS,4SR)-4-hydroxy-4-(3-hydroxyphenyl)-2-methyltetrahydropyran (3 g,84%), as a white solid.

Using the procedure described in Example 5, a portion (0.6 g) of theproduct so obtained was reacted with 2-bromomethyl-7-fluoronaphthalene(0.76 g) to give the required starting material (0.83 g, 79%), as anoil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6-1.75(m, 4H),2.05-2.2(m, 1H), 4.0(m, 3H), 5.25(s, 2H), 6.9-7.9(m, 10H).

l. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 1.15(d,3H), 1.6-2.05(m, 4H), 3.6(m, 2H), 3.85-4.1(m, 3H), 5.05-5.3 (m, 4H),5.75-5.95(m, 1H), 6.9-7.9(m, 9H).

The(2RS,4SR)-4-[3-(6,7-difluoronaphth-2-ylmethoxy)phenyl]-4-hydroxy-2-methyltetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in Example 5(2RS,4SR)-4-hydroxy-4-(3-hydroxyphenyl)-2-methyltetrahydropyran (0.3 g)was reacted with 2-bromomethyl-6,7-difluoronaphthalene (0.41 g) to givethe required starting material (0.33 g, 60%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.55-1.8(m, 4H),2.0-2.2(m, 1H), 3.9(m, 3H), 5.2(s, 2H), 6.9-7.8(m, 9H).

m. Ethyl iodide was used as the alkylating agent, potassium hydroxide asthe base and dimethylsulphoxide as the solvent, and the proceduredescribed in the 3rd paragraph of the portion of Note e. below Table IVin Example 15 was utilised. The product displayed the followingcharacteristic NMR signals (CDCl₃, delta values) 1.2(m, 5H), 1.5(t, 3H),1.9(m, 2H), 2.9(m, 2H), 3.85(m, 3H), 5.2(s, 2H), 6.18(m, 2H), 6.85(m,1H), 7.5(m, 3H), 7.87(m, 4H).

EXAMPLE 45

The procedure described in Example 5 was repeated using the appropriatealkyl bromide and the appropriate phenol. There were thus obtained thecompounds described in the following table:

                                      TABLE X                                     __________________________________________________________________________     ##STR12##                                                                    Ex. 45                                                                        Compd. No.                                                                           Ar.sup.1  Ar.sup.2        R.sup.1                                                                          R    m.p. (°C.)                                                                   Yield (%)                      __________________________________________________________________________    1.sup.a                                                                              7-fluoronaphth-2-yl                                                                     1,3-phenylene   Me alpha-Me                                                                           oil   77                             2.sup.b                                                                              7-fluoronaphth-2-yl                                                                     1,3-phenylene   Me beta-Me                                                                            oil   58                             3.sup.c                                                                              7-fluoronaphth-2-yl                                                                     1,3-phenylene   Et alpha-Me                                                                           oil   54                             4.sup.d                                                                              7-methylnaphth-2-yl                                                                     1,3-phenylene   Me alpha-Me                                                                           oil   80                             5.sup.e                                                                              7-methylnaphth-2-yl                                                                     1,3-phenylene   Me beta-Me                                                                            oil   48                             6.sup.f                                                                              7-methylnaphth-2-yl                                                                     1,3-phenylene   Et alpha-Me                                                                           oil   51                             7.sup.g                                                                              7-fluoronaphth-2-yl                                                                     5-fluoro-1,3-phenylene                                                                        Me alpha-Me                                                                           oil   83                             8.sup.h                                                                              7-fluoronaphth-2-yl                                                                     5-fluoro-1,3-phenylene                                                                        Me beta-Me                                                                            oil   85                             9.sup.i                                                                              7-fluoronaphth-2-yl                                                                     5-fluoro-1,3-phenylene                                                                        Et alpha-Me                                                                           oil   86                             10.sup.j                                                                             7-fluoronaphth-2-yl                                                                     5-trifluoro-methyl-1,3-phenylene                                                              Me alpha-Me                                                                           oil   86                             11.sup.k                                                                             7-fluoronaphth-2-yl                                                                     5-trifluoro-methyl-1,3-phenylene                                                              Me beta-Me                                                                            oil   80                             12.sup.l                                                                             7-fluoronaphth-2-yl                                                                     5-trifluoro-methyl-1,3-phenylene                                                              Et alpha-Me                                                                           oil   85                             13.sup.m                                                                             7-methylnaphth-2-yl                                                                     5-trifluoro-methyl-1,3-phenylene                                                              Me alpha-Me                                                                           oil   79                             __________________________________________________________________________

NOTES

a. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 1.55(m, 2H), 1.95(m, 2H), 2.95(s, 3H),3.9(m, 3H), 5.25(s, 2H), 6.9-7.9(m, 10H).

The (2RS,4SR)-4-(3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in Example 3,(2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.22g; obtained as described within Note k. below Table IX in Example 44)was reacted with methyl iodide (0.5 ml), to give(2RS,4SR)-4-(3-benzyloxyphenyl)-4-methoxy-2-methyltetrahydropyran (0.84g, 66%), as an oil.

Using the procedure also described within that Note k., the product soobtained was hydrogenolysed to give the required starting material (0.49g, 82%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.52-1.65(m, 1H),1.92-2.03(m, 3H), 3.0(s, 3H), 3.87-3.97(m, 3H), 5.36(s, 1H),6.73-7.27(m, 4H).

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.15(d, 3H), 1.6(t, 1H), 1.9(m, 1H), 2.3(t, 2H),2.85(s, 3H), 3.35(m, 2H), 3.9(d, 1H), 5.2(s, 2H), 6.9-7.9(m, 10H).

The (2SR,4SR)-4-(3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran usedas a starting material, was obtained using the procedures described inNote a. above except that(2SR,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.38g) was used as the starting material. There was thus obtained therequired starting material (0.52 g, 50%), as an oil.

c. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.05(t, 3H), 1.2(d, 3H), 1.55(t, 1H), 1.9(m, 3H),3.05(q, 2H), 3.9(m, 3H), 5.2(s, 2H), 6.9-7.05(m, 3H), 7.1-7.3(m, 2H),7.4-7.5(m, 2H), 7.8(m, 3H).

The (2RS,4SR)-4-ethoxy-4-(3-hydroxyphenyl)-2-methyltetrahydropyran, usedas a starting material, was obtained by repeating the proceduredescribed in Note a. above, except that ethyl iodide was used in placeof methyl iodide. There was thus obtained the required starting materialin 52% yield, as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1(t, 3H), 1.2(d, 3H), 1.5-1.65(m,2H), 1.9-2.0(m, 2H), 3.1(m, 2H), 3.9(m, 3H), 6.75-7.25(m, 4H).

d. The product displayed the following characteristic NMR signals(CDCl₃, delta values), 1.2(d, 3H), 1.5(m, 2H), 1.9-2.0 (m, 2H), 2.5(s,3H), 2.95(s, 3H), 3.9(m, 3H), 5.2(s, 2H), 6.9-7.85(m, 10H).

e. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.15(d, 3H), 1.6-2.0(m, 2H), 2.35(m, 2H), 2.5(s,3H), 2.85(s, 3H), 3.4(m, 2H), 3.9(m, 1H), 5.2(s, 2H), 6.9-7.8(m, 10H).

f. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.1(t, 3H), 1.2(d, 2H), 1.5-1.6(m, 1H), 1.9-2.0(m,3H), 2.5(s, 3H), 3.0-3.1(m, 2H), 3.9(m, 3H), 5.2(s, 2H), 6.9-7.85(m,10H).

g. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.20(d, 3H), 1.54(m, 1H), 1.86-1.98(m, 3H),2.96(s, 3H), 3.84-3.91(m, 3H), 5.2(s, 2H), 6.65(m, 1H), 6.73(m, 1H),6.85(m, 1H), 7.1-7.9(m, 6H).

h. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.18(d, 3H), 1.61(d of d's, 1H), 1.90(m, 1H),2.2-2.37(m, 2H), 2.88(s, 3H), 3.3-3.42(m, 2H), 3.9-3.99(m, 1H), 5.21(s,2H), 6.69(m, 1H), 6.77(m, 1H), 6.87(t, 1H), 7.1-7.9(m, 6H).

i. The product displayed the following charcteristic NMR signals (CDCl₃,delta values) 1.10(t, 3H), 1.23(d, 3H), 1.52(d of d's, 1H), 1.84-2.01(m,3H), 3.06(q, 2H), 3.81-4.01(m, 3H), 5.20(s, 2H), 6.63(m, 1H), 6.72(m,1H), 7.2-7.9(m, 6H).

The(2RS,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyranused as a starting material was obtained as follows:

The procedure described in the portion of Example 3 which is concernedwith the preparation of starting materials was repeated except that thediastereoisomers were not separated.

Using the procedure described in the 3rd paragraph of Note e. belowTable IV in Example 15, the mixture of isomers (4.5 g) was reacted withethyl iodide to give, after chromatography eluting with a 19:1 v/vmixture of toluene and ethyl acetate, a less polar isomer,(2RS,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-ethoxy-2-methyltetrahydropyran(0.7 g, 14%), as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer (2.6 g, 52%), as an oil.

Using the procedure described within Note k. below Table IX in Example44, the less polar isomer was hydrogenolysed to give the requiredstarting material (0.52 g, 96%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1(m, 6H), 1.54(d of d's, 1H),1.84-2.04(m, 3H), 3.13(q, 2H), 3.82-4.04(m, 3H), 6.47(m, 1H),6.63-6.77(m, 2H).

j. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 1.55(m, 1H), 1.9(m, 3H), 3.0(s, 3H),3.9(m, 3H), 5.3(s, 2H), 7.1-7.3(m, 4H), 7.4-7.55(m, 2H), 7.8-7.9(m, 3H).

The(2RS,4SR)-4-(3-hydroxy-5-trifluoromethylphenyl)-4-methoxy-2-methyltetrahydropyran,used as a starting material, was obtained as follows:

The procedure described in the second paragraph of Note e. below TableIV in Example 15 was repeated, except that3-benzyloxy-5-trifluoromethylbromobenzene (8.3 g) was used and2-methyltetrahydropyran-4-one was used in place oftetrahydropyran-4-one. There were thus obtained a less polar isomer,(2RS,4SR)-4-(3-benzyloxy-5-trifluoromethylphenyl)-4-hydroxy-2-methyltetrahydropyran(1.44 g, 16%), as an oil,

NMR Spectrum (CDCl₃, delta values, characteristic signals only) 1.25(d,3H), 3.95(m, 3H), 5.1(s, 2H), 7.0-7.5(m, 8H); and a more polar isomer,the corresponding (2SR,4SR)-isomer (2.66 g, 30%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6-2.1(m, 3H),2.2-2.4(m, 2H), 3.4(m, 2H), 3.9-4.05(m, 1H), 5.1(s, 2H), 7.15-7.5(m,8H).

Using the procedure described in Example 3, the (2RS,4SR)-isomer (1.4 g)was reacted with methyl iodide to give(2RS,4SR)-4-(3-benzyloxy-5-trifluoromethylphenyl)-4-methoxy-2-methyltetrahydropyran(0.9 g, 68%). as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.55(m, 1H), 1.85-2.0(m,3H), 2.95(s, 3H), 3.8-4.0(m, 3H), 5.1(s, 2H), 7.1-7.5(m, 8H).

Using the procedure described within Note k. below Table IX in Example44, the product so obtained was hydrogenolysed to give the requiredstarting material (0.63 g, 90%), as a solid.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6(m, 2H), 2.0(m, 3H),3.0(s, 3H), 3.85-4.0(m, 3H), 7.0-7.2(m, 3H).

k. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 1.65(m, 1H), 1.9-2.05(m, 1H), 2.35(m,2H), 2.9(s, 3H), 3.35(m, 2H), 3.95(m, 1H), 5.3(s, 2H), 7.1-7.9(m, 9H).

The(2SR,4SR)-4-(3-hydroxy-5-trifluoromethylphenyl)-4-methoxy-2-methyltetrahydropyran,used as a starting material, was obtained using the procedures describedin the last two paragraphs of Note j. above but taking the(2SR,4SR)-more polar isomer described therein as starting material.There was thus obtained the required starting material (88%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.25(m, 3H), 1.6-1.8(m, 1H),1.9-2.1(1H), 2.35(m, 2H), 2.9(s, 3H), 3.4(m, 2H), 3.95-4.1(m, 1H),7.0-7.2(m, 3H).

l. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.1(t, 3H), 1.2(d. 3H), 1.55(m, 1H), 1.9-2.05(m,3H), 3.1(m, 2H), 3.9(m, 3H), 5.28(s, 2H), 7.1-7.9(m, 9H).

The(2RS,4SR)-4-ethoxy-4-(3-hydroxy-5-trifluoromethylphenyl)-2-methyltetrahydropyran,used as a starting material, was obtained by repeating the proceduredescribed in the last two paragraphs of Note j. above, except that ethyliodide was used in place of methyl iodide. There was thus obtained therequired starting material in 56% yield, as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1-1.3(m, 6H), 1.55(m, 1H),1.9-2.05(m, 3H), 3.05-3.2(m, 2H), 3.85-4.05(m, 3H), 5.65(m, 1H),7.0-7.2(m, 3H).

m. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 1.2(d, 3H), 1.55(m, 2H), 1.9-2.0(m, 2H), 2.5(s,3H), 2.95(s, 3H), 3.85(m, 3H), 5.25(s, 2H), 7.1-7.9(m, 9H).

EXAMPLE 46

The procedure described in Example 5 was repeated except that(2RS,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyranwas used as the phenol component. There was thus obtained(2RS,4SR)-4-ethoxy-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-2-methyltetrahydropyran(41%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.1-1.2(m, 6H), 1.46-1.59(m, 2H),1.87-2.0(m, 2H), 3.11(q, 2H), 3.86-3.96(m, 3H), 4.90(s, 2H), 6.6-6.8(m,2H), 6.87(s, 1H), 7.25-7.45(m, 5H).

EXAMPLE 47

The procedure described in Example 5 was repeated except that(2SR,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyranwas used as the phenol component. There was thus obtained(2SR,4SR)-4-ethoxy-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-2-methyltetrahydropyran(61%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.01(t, 3H), 1.18(d, 3H), 1.63(m,1H), 1.96(m, 1H), 2.31(m, 2H), 3.07(q, 2H), 3.36-3.47(m, 2H),3.92-3.96(m, 1H), 4.91(s, 2H), 6.67-6.82(m, 2H), 6.91(s, 1H),7.25-7.45(m, 5H).

The(2SR,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran,used as a starting material, was obtained by hydrogenolysis of asolution of(2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-ethoxy-2-methyltetrahydropyran(2.6 g, described in Note i. below Table X in Example 45) in ethanol (25ml) in the presence of 10% palladium-on-charcoal catalyst (0.26 g). Themixture was filtered and the filtrate was evaporated. There was thusobtained the required starting material (1.69 g, 89%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.04(t, 3H), 1.21(d, 3H), 1.69(d ofd's, 1H), 1.98(m, 1H), 2.21-2.4(m, 2H), 3.12(q, 2H), 3.3-3.55(m, 2H),3.98(m, 1H), 6.51(m, 1H), 6.7(m, 1H), 6.77(s, 1H).

EXAMPLE 48

Using the procedure described in Example 3,4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g) wasreacted with methyl iodide (0.25 ml) to give4-(3-benzyloxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (1.06 g,89%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.18(s, 3H), 1.45(s, 3H), 1.71(d,1H), 1.93-2.03(m, 3H), 2.92(s, 3H), 3.66-3.77(m, 1H), 3.94-4.10(m, 1H),5.07(s, 2H), 6.88(d, 1H), 6.97(d, 1H), 7.02(s, 1H), 7.15-7.46(m, 6H).

The 4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran, used asa starting material, was obtained as follows:

A mixture of 2,3-dihydro-2,2-dimethylpyran-4-one (2.72 g, J. Org. Chem.,1963, 687), 10% palladium-on-charcoal catalyst (0.27 g) and ethanol (80ml) was stirred under an atmosphere of hydrogen for 6 hours. The mixturewas filtered and the filtrate was evaporated. There was thus obtained2,2-dimethyltetrahydropyran-4-one (2.05 g, 74%), as a liquid.

IR Spectrum 1730 cm⁻¹ (C═O).

Using the procedure described in the 2nd paragraph of the portion ofExample 3 which is concerned with the preparation of starting materials,3-benzyloxybromobenzene (1.34 g) was reacted with2,2-dimethyltetrahydropyran-4-one (0.65 g) to give4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g,72%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.20(s, 3H), 1.50(s, 3H), 1.52(m,1H), 1.57-1.73(m, 1H), 1.73-1.85(d, 2H), 2.08-2.27(m, 1H), 3.70-3.83(m,1H), 4.09-4.24(d of t's, 1H), 5.08(s, 2H), 6.88(d of d's, 1H), 7.07(d,1H), 7.14(t, 1H), 7.22-7.50(m, 6H).

EXAMPLE 49

Using the procedure described in Example 5, 2-bromomethylnaphthalene(0.245 g) was reacted with4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.25 g) togive4-methoxy-2,2-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran(0.38 g, 95%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.17(s, 3H), 1.45(s, 3H), 1.60(d,1H), 1.96-2.04(m, 3H), 2.92(s, 3H), 3.71(m, 1H), 4.06(m, 1H), 5.24(s,2H), 6.92(m, 1H), 6.97(m, 1H), 7.0(t, 1H), 7.28(t, 1H), 7.46-7.57(m,3H), 7.82-7.89(m, 4H).

The 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran, used as astarting material, was obtained as follows:

A mixture of 4-(3-benzyloxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran(1.06 g), 10% palladium-on-charcoal catalyst (0.44 g) and isopropanol(45 ml) was stirred under an atmosphere of hydrogen for 3 hours. Themixture was filtered and the filtrate was evaporated to give therequired starting material (0.74 g, 96%), which was used without furtherpurification.

EXAMPLE 50

Using the procedure described in Example 5,7-fluoro-2-bromomethylnaphthalene (0.23 g) was reacted with4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.21 g) togive4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,2-dimethyltetrahydropyran(0.35 g, 86%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(s, 3H), 1.49(s, 3H), 1.69-1.75(d,1H), 1.9-2.1(m, 3H), 2.95(s, 3H), 3.65-3.75(m, 1H), 3.9-4.1(m, 1H),5.25(s, 2H), 6.9-7.9(m, 10H).

EXAMPLE 51

The procedure described in Example 3 was repeated using the appropriatealkyl halide and the appropriate alcohol. There were thus obtained thecompounds described in the following table:

                  TABLE XI                                                        ______________________________________                                         ##STR13##                                                                    Ex. 51                                                                        Compd.                              m.p. Yield                                No.    Ar.sup.2    R.sup.1                                                                              R         (°C.)                                                                       (%)                                  ______________________________________                                         1.sup.a                                                                             1,3-phenylene                                                                             Me     alpha-ethyl                                                                             oil  83                                    2.sup.b                                                                             1,3-phenylene                                                                             Me     beta-ethyl                                                                              oil  71                                    3.sup.c                                                                             1,3-phenylene                                                                             Et     alpha-ethyl                                                                             oil  63                                    4.sup.d                                                                             1,3-phenylene                                                                             allyl  alpha-ethyl                                                                             oil  67                                    5.sup.e                                                                             5-fluoro-1,3-                                                                             Me     alpha-ethyl                                                                             oil  39                                          phenylene                                                               6.sup.f                                                                             5-fluoro-1,3-                                                                             allyl  alpha-ethyl                                                                             oil  84                                          phenylene                                                               7.sup.g                                                                             5-fluoro-1,3-                                                                             allyl  beta-ethyl                                                                              oil  18                                          phenylene                                                               8.sup.h                                                                             5-trifluoro-                                                                              allyl  alpha-ethyl                                                                             oil  28                                          methyl-                                                                       1,3-phenylene                                                           9.sup.i                                                                             1,3-phenylene                                                                             Me     alpha-n-propyl                                                                          oil  72                                   10.sup.j                                                                             1,3-phenylene                                                                             Me     beta-n-propyl                                                                           oil  85                                   11.sup.k                                                                             1,3-phenylene                                                                             allyl  alpha-n-propyl                                                                          oil  65                                   12.sup.l                                                                             1,3-phenylene                                                                             allyl  beta-n-propyl                                                                           oil  69                                   13.sup.m                                                                             5-fluoro-1,3-                                                                             Me     alpha-n-propyl                                                                          oil  48                                          phenylene                                                              14.sup.n                                                                             5-fluoro-1,3-                                                                             Me     beta-n-propyl                                                                           oil  53                                          phenylene                                                              15.sup.o                                                                             5-fluoro-1,3-                                                                             allyl  alpha-n-propyl                                                                          oil  48                                          phenylene                                                              16.sup.p                                                                             5-fluoro-1,3-                                                                             allyl  beta-n-propyl                                                                           oil  64                                          phenylene                                                              ______________________________________                                    

NOTES

a. Methyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.2-2.1(m, 6H), 2.9(s, 3H), 3.65(m, 1H), 3.9(m, 2H), 5.2(s, 2H),6.9-7.9(m, 1H).

The(2RS,4SR)-2-ethyl-4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,used as a starting material, was obtained by repeating the proceduredescribed in the portion of Note a. below Table IX in Example 44, exceptthat 2-ethyltetrahydropyran-4-one (Chem. Ber., 1955, 88, 1053) was usedin place of 2-methyltetrahydropyran-4-one. There were thus obtained: aless polar isomer,(2RS,4SR)-2-ethyl-4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyranin 26% yield, m.p. 85°-87° C., i.e. the 2-ethyl and 4-hydroxysubstituents are in trans-relationship; and a more polar isomer,(2SR,4SR)-2-ethyl-4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyranin 21% yield, m.p. 73°-75° C., i.e. the 2-ethyl and 4-hydroxysubstituents are in a cis-relationship.

b. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 0.9(t, 3H), 1.2-2.5(m, 6H), 2.85(s, 3H), 3.15(m,1H), 3.4(m, 1H), 3.95(m, 1H), 5.2(s, 2H), 6.9-7.9(m, 11H).

The (2SR,4SR)-isomer, described in Note a. above, was used as therequired starting material.

c. Ethyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values)0.9-2.05(m's, 12H), 3.1(q, 2H), 3.7(m, 1H), 3.9(m, 2H), 5.25(s, 2H),6.9-7.9(m, 11H).

d. Allyl bromide was used as the alkylating agent. The product displayedthe following charcteristic NMR signals (CDCl₃, delta values) 0.95(t,3H), 1.4-2.1(m, 6H), 3.6(m, 2H), 3.65(m, 1H), 3.9(m, 2H), 5.1-5.3(m,4H), 5.75-5.95(m, 1H), 6.9-7.9(m, 11H).

e. Methyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.4-2.0(m, 6H), 2.9(s, 3H), 3.4(m, 2H), 3.95(m, 1H), 5.2(s, 2H),6.65-7.9(m, 10H).

The(2RS,4SR)-2-ethyl-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydropyran,used as a starting material, was obtained using5-fluoro-3-(naphth-2-ylmethoxy)bromobenzene and2-ethyltetrahydropyran-4-one as the starting materials and using theprocedure described in the portion of Note a. below Table IX in Example44. There were thus obtained: a less polar isomer,(2RS,4SR)-2-ethyl-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydrofuranin 13% yield, as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer, in 12% yield, as an oil.

f. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.5(m, 4H), 1.9(m, 2H), 3.6(m, 2H), 3.7(m, 1H), 3.9(m, 2H), 5.2(m,4H), 5.84(m, 1H), 6.6-7.9(m, 10H).

g. Allyl bromide was used as the alkylating agent. The product displayedthe following charcteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.4(m, 2H), 1.65(m, 1H), 1.95(m, 1H), 2.28(m, 2H), 3.0-3.4(m, 2H),3.5(m, 2H), 3.9(m, 1H), 5.05(m, 2H), 5.2(s, 2H), 5.7(m, 1H), 6.6-7.9(m,10H).

The (2SR,4SR)-isomer, described in Note e above, was used as therequired starting material.

h. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.95(t,3H), 1.4-2.1(m, 8H), 3.6(m, 1H), 3.9(m, 2H), 5.2(m, 2H), 5.8(m, 1H),5.3(s, 2H), 7.1-7.9(m, 10H).

The(2RS,4SR)-2-ethyl-4-hydroxy-4-[3-(naphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyran,used as a starting material, was obtained, using the procedure describedin the portion of Note a. below Table IX in Example 44, and using3-(naphth-2-ylmethoxy)-5-trifluoromethylbromobenzene and2-ethyltetrahydropyran-4-one as the starting materials. There were thusobtained: a less polar isomer(2RS,4SR)-2-ethyl-4-hydroxy-4-[3-(naphth-2-ylmethoxy)-5-trifluorophenyl]tetrahydropyranin 4% yield, as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer, in 11% yield, as an oil.

i. Methyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.4(m, 4H), 1.55(m, 2H), 1.95(m, 2H), 3.0(s, 3H), 3.85(m, 3H),5.2(s, 2H), 7.0-7.9(m, 11H).

The(2RS,4SR)-4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]-2-n-propyltetrahydropyran,used as a starting material, was obtained by repeating the proceduredescribed in the portion of Note a. below Table IX in Example 44, exceptthat 2-n-propyltetrahydropyran-4-one (Chem. Ber., 1955, 88, 1053) wasused in place of 2-methyltetrahydropyran-4-one. There were thusobtained: a less polar isomer,(2RS,4SR)-4-hydroxy-4-[3-(naphth-2-ylmethoxy)phenyl]-2-n-propyltetrahydropyranin 18% yield, as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer in 11% yield, as an oil.

j. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 0.9(t, 3H), 1.4(m, 4H), 2.0-2.4(m, 4H), 2.9(m,2H), 3.4(m, 2H), 3.9(m, 1H), 5.2(s, 2H), 7.0-7.9(m, 11H).

The (2SR,4SR)-isomer, described in Note i. above, was used as therequired starting material.

k. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.45(m, 6H), 1.95(m, 2H), 3.6(m, 2H), 3.9(m, 3H), 5.2(m, 4H),5.8(m, 1H), 7.0-7.9(m, 11H).

l. The product displayed the following charcteristic NMR signals (CDCl₃,delta values) 0.9(t, 3H), 1.4(m, 4H), 1.7-1.9(m, 2H), 2.34(m, 2H),3.4(m, 2H), 3.5(m, 2H), 3.9(m, 1H), 5.1(m, 2H), 5.2(s, 2H), 5.7(m, 1H),7.0-7.9(m, 11H).

m. Methyl iodide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.4(m, 4H), 1.5-1.9(m, 4H), 3.0(s, 3H), 3.8(m, 3H), 5.2(s, 2H),6.6-7.9(m, 10H).

The(2RS,4SR)-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxy-2-n-propyltetrahydropyran,used as a starting material, was obtained, using the procedure describedin the portion of Note a. below Table IX in Example 44, and using5-fluoro-3-(naphth-2-ylmethoxy)bromobenzene and2-n-propyltetrahydropyran-4-one as the starting materials. There werethus obtained: a less polar isomer,(2RS,4SR)-4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxy-2-n-propyltetrahydropyranin 17% yield, as an oil; and a more polar isomer, the corresponding(2SR,4SR)-isomer, in 10% yield, as an oil.

n. The product displayed the following characteristic NMR signals(CDCl₃, delta values) 0.9(t, 3H), 1.5-1.9(m, 6H). 2.28(m, 2H) 2.9(s,3H), 3.3(m, 2H), 3.9(m, 1H), 5.2(s, 2H), 6.6-7.9(m, 10H).

o. Allyl bromide was used as the alkylating agent. The product displayedthe following characteristic NMR signals (CDCl₃, delta values) 0.9(t,3H), 1.4-1.9(m, 8H), 3.6(m, 2H), 3.9(m, 3H), 5.2(m, 4H), 5.7(m, 3H),6.6-7.9(m, 10H).

p. The product displayed the following charcteristic NMR signals (CDCl₃,delta values) 0.9(t, 3H), 1.4(m, 4H), 1.7-1.9(m, 2H), 2.3(m, 2H), 3.4(m,2H), 3.6(m, 2H), 3.94(m, 1H), 5.1(m, 2H), 5.2(s, 2H), 5.7(m, 1H),6.7-7.9(m, 10H).

EXAMPLE 52

Using the procedure described in Example 5, 2-bromomethylnaphthalene(0.234 g) was reacted with4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.2 g, lesspolar isomer) to give4-methoxy-2,6-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran(0.29 g, 92%), m.p. 105°-107° C.

The 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (lesspolar isomer), used as a starting material, was obtained as follows:

A solution of 2,6-dimethyltetrahydropyran-4-one (2.2 g) intetrahydrofuran (5 ml) was added to a solution of3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of3-benzyloxybromobenzene (5 g), magnesium (0.5 g) and tetrahydrofuran (20ml)] in tetrahydrofuran and the mixture was stirred at ambienttemperature for 3 hours. The mixture was cooled to 5° C., ice (5 ml) and2N hydrochloric acid solution (25 ml) were added, and the mixture wasextracted with ethyl acetate. The organic phase was washed with asaturated sodium chloride solution, dried (MgSO₄) and evaporated. Theresidue was purifed by column chromatography using increasingly polarmixtures of toluene and ethyl acetate as eluent. There were thusobtained two isomers of4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran: a lesspolar isomer (2.41 g, 45%),

NMR Spectrum (CDCl₃, delta values) 1.2-1.3(d, 6H), 1.6(broad s, 1H),1.7(m, 4H), 3.95-4.1(m, 2H), 5.1(s, 2H), 6.9-7.5(m, 9H); and a morepolar isomer (1.57 g, 29%),

NMR Spectrum (CDCl₃, delta values) 1.2(d, 6H), 1.55-1.9(m, 3H),2.3-2.4(m, 2H), 3.3-3.5(m, 2H), 5.1(s, 2H), 6.9-7.5(m, 9H).

Using the procedure described in Example 3, the less polar isomer soobtained was reacted with methyl iodide to give4-(3-benzyloxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (80%), as anoil.

Using the procedure described within Note k. below Table IX in Example44, the product so obtained was hydrogenolysed to give the requiredstarting material (92%), as an oil.

EXAMPLE 53

Using the procedure described in Example 5,7-fluoro-2-bromomethylnaphthalene (0.265 g) was reacted with4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.225 g, lesspolar isomer) to give4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,6-dimethyltetrahydropyran(0.37 g, 93%), as an oil.

NMR Spectrum (CDCl₃, delta values) 1.2(d, 6H), 1.5-1.6(m, 3H),1.9-2.1(d, 1H), 3.0(s, 3H), 3.85-4.05(m, 2H), 5.2(s, 2H), 6.8-7.9(m,10H).

EXAMPLE 54

Using the procedure described in Example 5,7-fluoro-2-bromomethylnaphthalene (0.5 g) was reacted with4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.45 g, morepolar isomer) to give4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,6-dimethyltetrahydropyran(0.74 g, 77%), as an oil which crystallised on standing, m.p. 77° C.

The 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (morepolar isomer), used as a starting material, was obtained as follows:

Using the procedure described in Example 3, the more polar isomer of4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran (describedin the portion of Example 52 which is concerned with the preparation ofstarting materials) was reacted with methyl iodide to give4-(3-benzyloxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran, (77%, morepolar isomer), as an oil.

Using the procedure described within Note k. below Table IX in Example44, the product so obtained was hydrogenolysed to give the requiredstarting material (93%), as an oil.

EXAMPLE 55

Using the procedure described in Example 5,4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with5-bromo-2-bromomethylnaphthalene to give4-[3-(5-bromonaphth-2-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyranin 52% yield, as an oil.

NMR Spectrum (CDCl₃, delta values) 1.8-2.1(m, 4H), 2.95(s, 3H),3.75-3.90(m, 4H), 5.25(s, 2H), 6.6-8.25(m, 9H).

The 5-bromo-2-bromomethylnaphthalene, used as a starting material, wasobtained as follows:

6-Methyl-1-naphthoic acid (6 g; J. Amer. Chem. Soc., 1941, 63, 1857) wasadded to thionyl chloride (50 ml) and the mixture was heated to refluxfor 30 minutes. The solution was evaporated to give 6-methyl-1-naphthoylchloride.

A solution of a mixture of the product so obtained and2,2'-azobisisobutyronitrile (1.62 g) in bromotrichloromethane (5 ml) wasadded dropwise to a suspension of the sodium salt of2-mercaptopyridine-N-oxide (4.84 g) in bromotrichloromethane (50 ml)which was stirred and heated to 100° C. The mixture was heated to 100°C. for 2 hours and then stirred at ambient temperature for 16 hours. Themixture was partitioned between methylene chloride and water. Theorganic layer was washed with 2N aqueous hydrochloric acid solution,with 2N aqueous sodium hydroxide solution and with water, dried (MgSO₄)and evaporated. The residue was purified by column chromatography usinghexane as eluent to give 1-bromo-6-methylnaphthalene (2.79 g, 40%), as aliquid.

A mixture of a portion (1 g) of the product so obtained,N-bromosuccinimide (0.81 g), 2,2'-azobisisobutyronitrile (0.05 g) andcarbon tetrachloride (25 ml) was heated to reflux and irradiated withlight from a 275 watt bulb for 1 hour. The mixture was cooled to ambienttemperature and filtered. The filtrate was evaporated and the residuewas purified by column chromatography using hexane as eluent. There wasthus obtained the required starting material (0.84 g, 61%), m.p.110°-114° C.

EXAMPLE 56

Using the procedure described in Example 5,4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with2-bromomethyl-5-trifluoromethylnaphthalene to give4-[5-fluoro-3-(5-trifluoromethylnaphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyranin 36% yield, as an oil.

NMR Spectrum (CD₃ SOCD₃, delta values) 1.8-2.0 (m, 4H), 2.85 (s, 3H),3.4-3.7 (m, 4H), 5.25 (s, 2H), 6.75-7.0 (m, 3H), 7.6-8.3 (m, 6H).

The 2-bromomethyl-5-trifluoromethylnaphthalene, used as a startingmaterial, was obtained as follows:

Sodium trifluoroacetate (4.41 g) and cuprous iodide (3.08 g) were addedin turn to a solution of 1-bromo-6-methylnaphthalene (1.79 g) inN,N-dimethylacetamide (36 ml) and the mixture was heated to reflux for10 hours. The mixture was cooled to ambient temperature and filtered.The filtrate was evaporated and the residue was partitioned betweendiethyl ether and water. The organic layer was washed with water andwith a saturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usinghexane as eluent. There was thus obtained6-methyl-1-trifluoromethylnaphthalene (1 g, 59%), as an oil.

Using a similar procedure to that described in the last paragraph ofExample 55 above, except that the reaction mixture was heated to refluxfor 24 hours, the product so obtained was brominated to give therequired starting material (0.7 g, 52%), m.p. 48°-65° C.

EXAMPLE 57

Using the procedure described in Example 3,(2R,4S)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyranwas reacted with methyl iodide to give(2R,4S)-4-methoxy-2-methyl-4-[3-naphth-2-ylmethoxy)phenyl]tetrahydropyranin 82% yield, m.p. 60°-62° C., [α]²⁰ =-2.5° (chloroform, c=2 g/100 ml).

The(2R,4S)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,used as a starting material, was obtained as follows:

Using the procedure described in the portion of Example 3 which isconcerned with the preparation of starting materials,3-(naphth-2-ylmethoxy)bromobenzene was converted into3-(naphth-2-ylmethoxy)phenyl-lithium which was reacted with(-)-(R)-2-methyltetrahydropyran-4-one (J. Amer. Chem. Soc., 1982, 104,4670). There were thus obtained:

a less polar isomer,(2R,4S)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,in 20% yield, m.p. 94°-96° C., i.e. the 2-methyl and 4-hydroxy groupsare in a trans-relationship; and a more polar isomer,(2R,4R)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,in 22% yield, m.p. 105°-109° C., i.e. the 2-methyl and 4-hydroxy groupsare in a cis-relationship.

EXAMPLE 58

Using the procedure described in Example 3,(2R,4R)-4-hydroxy-2-methyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyranwas reacted with methyl iodide to give(2R,4R)-4-methoxy-2-methyl-4-[3-(naphth-2-ylmethoxyphenyl]tetrahydropyranin 73% yield, as an oil. [α]²⁰ =+8.5° (chloroform, c=2 g/100 ml).

NMR Spectrum (CDCl₃, delta values) 1.2(d, 3H), 1.6-2.4(m, 4H), 2.8(s,3H), 3.4(m, 2H), 3.9(m, 4H), 5.2(s, 2H), 6.9-8.0(m, 11H).

EXAMPLE 59

A mixture of 4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]thiacyclohexane(0.364 g; Example 2, Compound No. 3), m-chloroperbenzoic acid (0.344 g)and methylene chloride (4 ml) was stirred at ambient temperature for 4hours. The mixture was partitioned between methylene chloride and asaturated aqueous sodium chloride solution. The organic phase was washedwith a saturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usinginitially a 4:1 v/v mixture of methylene chloride and diethyl ether andthen a 4:1 v/v mixture of methylene chloride and acetone as eluent.There were thus obtained:

4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]thiacyclohexane 1-oxide 0.1 g,25%), m.p. 141°-142° C.; and

4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]thiacyclohexane 1,1-dioxide(0.1 g, 25%), m.p. 110°-111° C.

EXAMPLE 60

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt salt thereof (hereafter compound X), for therapeutic orprophylactic use in humans:

    ______________________________________                                        (a)   Tablet I              mg/tablet                                               Compound X             100                                                    Lactose Ph.Eur         182.75                                                 Croscarmellose sodium  12.0                                                   Maize starch paste      2.25                                                  (5% w/v paste)                                                                Magnesium stearate      3.0                                             (b)   Tablet II             mg/tablet                                               Compound X             50                                                     Lactose Ph.Eur         223.75                                                 Croscarmellose sodium   6.0                                                   Maize starch           15.0                                                   Polyvinylpyrrolidone    2.25                                                  (5% w/v paste)                                                                Magnesium stearate      3.0                                             (c)   Tablet III            mg/tablet                                               Compound X              1.0                                                   Lactose Ph.Eur         93.25                                                  Croscarmellose sodium   4.0                                                   Maize starch paste      0.75                                                  (5% w/v paste)                                                                Magnesium stearate      1.0                                             (d)   Capsule               mg/capsule                                              Compound X             10 mg                                                  Lactose Ph.Eur         488.5                                                  Magnesium stearate      1.5                                             (e)   Injection I           (50 mg/ml)                                              Compound X              5.0% w/v                                              1M Sodium hydroxide solution                                                                         15.0% v/v                                              0.1M Hydrochloric acid                                                        (to adjust pH to 7.6)                                                         Polyethylene glycol 400                                                                               4.5% w/v                                              Water for injection to 100%                                             (f)   Injection II          (10 mg/ml)                                              Compound X              1.0% w/v                                              Sodium phosphate BP     3.6% w/v                                              0.1M Sodium hydroxide solution                                                                       15.0% v/v                                              Water for injection to 100%                                                                         (1 mg/ml,                                         (g)   Injection III         buffered to pH 6)                                       Compound X              0.1% w/v                                              Sodium phosphate BP     2.26% w/v                                             Citric acid             0.38% w/v                                             Polyethylene glycol 400                                                                               3.5% w/v                                              Water for injection to 100%                                             (h)   Aerosol I             mg/ml                                                   Compound X             10.0                                                   Sorbitan trioleate     13.5                                                   Trichlorofluoromethane                                                                               910.0                                                  Dichlorodifluoromethane                                                                              490.0                                            (i)   Aerosol II            mg/ml                                                   Compound X              0.2                                                   Sorbitan trioleate      0.27                                                  Trichlorofluoromethane                                                                               70.0                                                   Dichlorodifluoromethane                                                                              280.0                                                  Dichlorotetrafluoroethane                                                                           1094.0                                            (j)   Aerosol III           mg/ml                                                   Compound X              2.5                                                   Sorbitan trioleate      3.38                                                  Trichlorofluoromethane                                                                               67.5                                                   Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                            191.6                                            (k)   Aerosol IV            mg/ml                                                   Compound X              2.5                                                   Soya lecithin           2.7                                                   Trichlorofluoromethane                                                                               67.5                                                   Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                            191.6                                            ______________________________________                                         Note                                                                          The above formulations may be obtained by conventional procedures well        known in the pharmaceutical art. The tablets (a)-(c) may be enteric coate     by conventional means, for example to provide a coating of cellulose          acetate phthalate. The aerosol formulations (h)-(k) may be used in            conjunction with standard, metered dose aerosol dispensers, and the           suspending agents sorbitan trioleate and soya lecithin may be replaced by     an alternative suspending agent such as sorbitan monooleate , sorbitan        sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.         

    ______________________________________                                        CHEMICAL FORMULAE                                                             ______________________________________                                                            Sheet 1/2                                                  ##STR14##          I                                                          ##STR15##          II                                                         ##STR16##          III                                                        ##STR17##          IV                                                         ##STR18##          V                                                                             Sheet 2/2                                                  ##STR19##          VI                                                        ______________________________________                                    

What we claim is:
 1. A heterocyclic derivative of the formula I##STR20## wherein Ar¹ is phenyl or naphthyl which may optionally bearone or more substituents selected from amino, halogeno, hydroxy,carboxy, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkysulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl,(2-4C)alkanoyl, (2-4C)alkanoylamino, hydroxy-(1-4C)alkyl,fluoro-(1-4C)alkyl, amino-(1-4C)alkyl, cyano-(1-4C)alkyl andcyano-(1-4C)alkoxy;wherein A¹ is (1-6C)alkylene, (3-6C)alkenylene,(3-6C)alkynylene or cyclo(3-6C)alkylene; wherein Ar² is phenylene whichmay optionally bear one or two substituents selected from halogeno,hydroxy, amino, nitro, cyano, carbamoyl, ureido, (1-4C)alkyl,(3-4C)alkenyloxy, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkysulphinyl,(1-4C)alkylsulphonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,fluoro-(1-4C)alkyl, (1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy,hydroxy-(2-4C)alkylamino, cyano-(1-4C)alkylamino,carboxy-(1-4C)alkylamino and (1-4C)alkoxycarbonyl-(1-4C)alkylamino;wherein R¹ is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl,cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoyl which mayoptionally bear a substituent selected from halogeno, (1-4C)alkyl and(1-4C)alkoxy; and wherein R² and R³ together form a group of the formula--A² -X-A³ - which, together with the carbon atom to which A² and A³ areattached, defines a ring having 6 ring atoms, wherein A² and A³, whichmay be the same or different, each is (1-4C)alkylene and X is oxy, andwhich ring may bear one, two or three substituents, which may be thesame or different, selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy,(3-4C)alkenyloxy and (3-4C)alkynyloxy;or a pharmaceutically-acceptablesalt thereof.
 2. A heterocyclic derivative of the formula I as claimedin claim 1wherein Ar¹ is phenyl or naphthyl which may optionally bearone or more substituents selected from halogeno, hydroxy, carboxy,cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkysulphinyl, (1-4C)alkylsulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (1-4C)alkoxycarbonyl,(2-4C)alkanoyl, hydroxy-(1-4C)alkyl and fluoro-(1-4C)alkyl; wherein A¹is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene orcyclo(3-6C)alkylene; wherein Ar² is phenylene which may optionally bearone or two substituents selected from halogeno, hydroxy, amino, nitro,cyano, carbamoyl, (1-4C)alkyl, (3-4C)alkenyl, (1-4C)alkoxy,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkysulphonyl,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl,(1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy,carbamoyl-(1-4C)alkoxy and (1-4C)alkoxycarbonyl-(1-4C)alkoxy; wherein R¹is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl,cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R¹ is benzoyl which mayoptionally bear a substituent selected from halogeno, (1-4C)alkyl and(1-4C)alkoxy; and wherein R² and R³ together a group of the formula --A²-X-A³ - which, together with the carbon atom to which A² and A³ areattached, defines a ring having 6 ring atoms, wherein A² and A³, whichmay be the same or different, each is (1-4C)alkylene and X is oxy;or apharmaceutically-acceptable salt thereof.
 3. A heterocyclic derivativeof the formula I as claimed in claim 1 whereinAr¹ is phenyl ornaphth-2-yl which may optionally bear one or two substituents selectedfrom amino, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, methoxy, methylthio, methylsulphinyl,methylsulphonyl, difluoromethyl, trifluoromethyl, cyanomethyl,1-cyanoethyl, 2-cyanoprop-2-yl, cyanomethoxy and 2-cyanoethoxy; A¹ ismethylene, 1-propenylene or 1-propynylene; Ar² is 1,3-phenylene or1,4-phenylene which may optionally bear one substituent selected fromfluoro, hydroxy, amino, nitro, ureido, methoxy, methylamino,dimethylamino, trifluoromethyl, acetamido, cyanomethoxy,2-hydroxyethylamino, cyanomethylamino and carboxymethylamino; R¹ ishydrogen, methyl, ethyl, allyl or 2-propynyl; and R² and R³ togetherform a group of the formula --A² -X-A³ - which, together with the carbonatom to which A² and A³ are attached, defines a ring having 6 ringatoms, wherein A² is ethylene, A³ is ethylene, and X is oxy, and whichring may bear one or two substituents, which may be the same ordifferent, selected from hydroxy, methyl, ethyl, propyl and methoxy; ora pharmaceutically-acceptable salt thereof.
 4. A heterocyclic derivativeof the formula I as claimed in claim 1 whereinAr¹ is phenyl ornaphth-2-yl which may optionally bear one or two substituents selectedfrom fluoro, chloro, bromo, cyano, methyl, ethyl, tert-butyl,methylthio, methylsulphinyl, difluoromethyl, trifluoromethyl andcyanomethoxy; A¹ is methylene or 1-propynylene; Ar² is 1,3-phenylenewhich may optionally bear one substituent selected from fluoro, amino,nitro, ureido, dimethylamino, trifluoromethyl and cyanomethylamino; R¹is methyl, ethyl or allyl; and R² and R³ together form a group of theformula --A² -X-A³ - which, together with the carbon atom to which A²and A³ are attached, defines a ring having 6 ring atoms, wherein A² isethylene, A³ is ethylene and X is oxy, and which ring may bear a methylor ethyl substituent alpha to X;or a pharmaceutically-acceptable saltthereof.
 5. A heterocyclic derivative of the formula I as claimed inclaim 1 whereinAr¹ is phenyl, 4-fluorophenyl, 2,4-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 2,5-dimethylphenyl,4-ethylphenyl, 4-tert-butylphenyl, 4-methylthiophenyl,4-methylsulphinylphenyl, 2-trifluoromethylphenyl, 2-cyanomethoxyphenyl,3-cyanomethoxyphenyl, 2-cyano-3-fluorophenyl or2-methylthio-5-trifluoromethylphenyl; A¹ is 1-propynylene; Ar² is1,3-phenylene, 5-fluoro-1,3-phenylene, 5-amino-1,3-phenylene,5-nitro-1,3-phenylene, 5-ureido-1,3-phenylene,5-dimethylamino-1,3-phenylene, 5-trifluoromethyl-1,3-phenylene,5-acetamido-1,3-phenylene, 5-(2-hydroxyethylamino)-1,3-phenylene or5-cyanomethylamino-1,3-phenylene; R¹ is methyl, ethyl or allyl; and R²and R³ together form a group of the formula --A² -X-A³ - which, togetherwith the carbon atom to which A² and A³ are attached, defines a ringhaving 6 ring atoms, wherein each of A² and A³ is ethylene and X is oxy,and which ring may bear a methyl or ethyl substituent alpha to X;or apharmaceutically-acceptable salt thereof.
 6. A heterocyclic derivativeof the formula I as claimed in claim 1 whereinAr¹ is naphth-2-yl,7-fluoronaphth-2-yl, 6,7-difluoronaphth-2-yl, 7-methylnaphth-2-yl,7-difluoromethylnaphth-2-yl, 5-bromonaphth-2-yl or5-trifluoromethylnaphth-2-yl; A¹ is methylene; Ar² is 1,3-phenylene,5-fluoro-1,3-phenylene or 5-trifluoromethyl-1,3-phenylene; R¹ is methyl,ethyl or allyl; and R² and R³ together form a group of the formula --A²-X-A³ - which, together with the carbon atom to which A² and A³ areattached, defines a ring having 6 ring atoms, wherein each of A² and A³is ethylene and X is oxy, and which ring may bear a methyl or ethylsubstituent alpha to X;or a pharmaceutically-acceptable salt thereof. 7.A heterocyclic derivative of the formula I as claimed in claim 1selected from the group consistingof:4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran,(2RS,4SR)-4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxy-2-methyltetrahydropyran,4-[5-fluoro-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,4-[5-amino-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,4-methoxy-4-[3-(3-phenylprop-2-ynyloxy)-5-trifluoromethylphenyl]tetrahydropyran,4-[5-fluoro-3-(3-(4-fluorophenyl)prop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,4-[5-(2-hydroxyethylamino)-3-(3-phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,4-methoxy-4-[3-(3-phenylprop-2-ynyloxy)-5-ureidophenyl]tetrahydropyran,4-[3-(3-(2-chlorophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran,4-[5-fluoro-3-(3-(2-trifluoromethyl)phenylprop-2-ynyloxy)phenyl]-4-methoxytetrahydropyran,4-[3-(3-(3,5-dichlorophenyl)prop-2-ynyloxy)-5-fluorophenyl]-4-methoxytetrahydropyran,4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxytetrahydropyran,4-allyloxy-4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]tetrahydropyran,4-[3-(5-bromonaphth-2-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyran,(2RS,4SR)-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran,(2RS,4SR)-4-methoxy-2-methyl-4-[3-(7-methylnaphth-2-ylmethoxy)phenyl]tetrahydropyran,(2RS,4SR)-4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxy-2-methyltetrahydropyran,(2RS,4SR)-4-ethoxy-4-[3-(7-fluoronaphth-2-ylmethoxy)-5-trifluoromethylphenyl]-2-methyltetrahydropyran,(2RS,4SR)-4-[5-fluoro-3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran,(2RS,4SR)-4-ethoxy-4-[5-fluoro-3-(7-fluoronaphth-2-ylmethoxy)phenyl]-2-methyltetrahydropyran,(2RS,4SR)-4-allyloxy-4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-2-methyltetrahydropyranand(2RS,4SR)-4-allyloxy-2-ethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran.or a pharmaceutically-acceptable salt thereof.
 8. A pharmaceuticalcomposition suitable for use in providing inhibition of 5-lipoxygenasewhich comprises an effective amount of a heterocyclic derivative of theformula I, or a pharamaceutically-acceptable salt thereof, as claimed inany one of claims 1 to 7 in association with apharmaceutically-acceptable diluent or carrier.
 9. A method of treatinga disease or medical condition mediated alone or in part by one or moreleukotrienes which comprises administering to a warm-blooded animalrequiring such treatment a 5-lipoxygenase-inhibitory amount of aheterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof, as claimed in any one ofclaims 1 to 7.